EP0352575A2 - Substituted annealed pyrroles - Google Patents

Abstract

Substituted fused pyrroles can be prepared by reducing corresponding ketones and subsequent saponification, cyclization, hydrogenation and, if appropriate, isomer separation. The new substituted fused pyrroles can be used in drugs.

Description

The invention relates to substituted fused pyrroles, intermediates for their preparation and their use in medicaments.

It is known that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) [Mevinolin, EP 22 478, US 4,231,938]. In addition, certain indole derivatives or pyrazole derivatives [EP-A 1 114 027; US 4,613,610] and pyrrole derivatives [EP-A 1 0 221 025] inhibitors of HMB-CoA reductase.

in welcher

• R' - Heteroaryl bedeutet, das bis zu 3-fach gleich oder verschieden durch Halogen, Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl. Aryl, Aryloxy, Arylthio, Arylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl oder durch eine Gruppe der Formel -NR⁷R⁸ substituiert sein kann, worin
• R⁷, R^{8 -} gleich oder verschieden sind und für Alkyl, Aryl, Aralkyl, Acyl, Alkylsulfonyl oder Arylsulfonyl stehen, oder
• R' - Aryl bedeutet, das bis zu 5-fach gleich oder verschieden substituiert sein kann durch Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkyl, Aralkoxy, Aralkylthio, Aralkylsulfonyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl, Sulfamoyl, Dialkylsulfamoyl, Carbamoyl, Dialkylcarbamoyl oder durch eine Gruppe der Formel -NR⁷R⁸, worin
• R7 und R⁸ die oben angegebene Bedeutung haben,
• R^{2 -} Heteroaryl bedeutet, das bis zu 3-fach gleich oder verschieden durch Halogen, Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl. Aryl, Aryloxy, Arylthio, Arylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl oder durch eine Gruppe der Formel -NR⁷R⁸ substituiert sein kann, worin
• R⁷, R^{8 -} die oben angegebene Bedeutung haben, oder
  • - Aryl bedeutet, das bis zu 5-fach gleich oder verschieden substituiert sein kann durch Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkyl, Aralkoxy, Aralkylthio, Aralkylsulfonyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl, Sulfamoyl, Dialkylsulfamoyl, Carbamoyl, Dialkylcarbamoyl oder durch eine Gruppe der Formel -NR⁷R⁸, worin
• R⁷ und R⁸ die oben angegebene Bedeutung haben, oder
  • - Cycloalkyl bedeutet, oder
  • - Alkyl bedeutet, das substituiert sein kann durch Halogen, Cyano, Alkoxy, Alkylthio, Alkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Trifluormethylsulfonyl, Alkoxycarbonyl, Acyl oder durch eine Gruppe der Formel -NR'R⁸, worin
• R⁷, R^{8 -} die oben angegebene Bedeutung haben, oder durch Carbamoyl, Dialkylcarbamoyl, Sulfamoyl, Dialkylsulfamoyl, Heteroaryl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkoxy, Aralkylthio oder Aralkylsulfonyl, wobei die Heteroaryl- und Arylreste der letztgenannten Substituenten bis zu 3-fach gleich oder verschieden durch Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Alkyl, Alkoxy, Alkylthio oder Alkylsulfonyl substituiert sein können,
• _R3, _R ⁴, R⁵, R⁶ gleich oder verschieden sind und
  • - Wasserstoff bedeuten, oder
  • - Cycloalkyl bedeutet, oder
  • - Alkyl bedeuten, das substituiert sein kann durch Halogen, Cyano, Alkoxy, Alkylthio, Alkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Trifluormethylsulfonyl, Alkoxycarbonyl, Acyl oder durch eine Gruppe der Formel -NR'R⁸, worin
• R⁷, R⁸ die oben angegebene Bedeutung haben, oder durch Carbamoyl, Dialkylcarbamoyl, Sulfamoyl, Dialkylsulfamoyl, Heteroaryl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkoxy, Aralkylthio oder Aralkylsulfonyl, wobei die Heteroaryl- und Arylreste bis zu 3-fach gleich oder verschieden durch Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Alkyl, Alkoxy, Alkylthio oder Alkylsulfonyl substituiert sein können, oder
  • - Heteroaryl bedeuten, das bis zu 3-fach gleich oder verschieden durch Halogen, Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl oder durch eine Gruppe der Formel -NR⁷R⁸ substituiert sein kann, worin
• R⁷ und R⁸ die oben angegebene Bedeutung haben, oder
  • - Aryl bedeuten, das bis zu 5-fach gleich oder verschieden substituiert sein kann durch Alkyl, Alkoxy, Alkylthio, Alkylsulfonyl, Aryl, Aryloxy, Arylthio, Arylsulfonyl, Aralkyl, Aralkoxy, Aralkylthio, Aralkylsulfonyl, Halogen, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Alkoxycarbonyl, Sulfamoyl, Dialkylsulfamoyl, Carbamoyl, Dialkylcarbamoyl oder durch eine Gruppe der Formel -NR⁷R⁸, worin
• R⁷ und R⁸ die oben angegebene Bedeutung haben, oder
• R³ und R⁴ und/oder R⁵ und R⁶ jeweils gemeinsam einen Ring bilden, der gegebenenfalls durch ein Sauerstoffatom, ein Schwefelatom, oder eine Gruppe der Formel -NR⁹ unterbrochen sein kann, worin
• R^{9 -} für Wasserstoff, Alkyl, Aryl, Carbamoyl oder Alkoxycarbonyl steht,
• X - eine Gruppe der Formel -CH₂-CH₂- oder -CH = CH- bedeutet,
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R'^{o -} für Wasserstoff oder Alkyl steht, und
• R" - für Wasserstoff steht, oder
  • - für Alkyl, Aralkyl oder Aryl steht, oder
  • - für ein Kation steht,
• Y - eine Bindung bedeutet, oder
  • - eine Gruppe der Formel -NR'² bedeutet worin
• R^{12 -} für Wasserstoff oder Alkyl steht,
• Z - eine Gruppe der Formel -CH = CH- oder -CH₂- bedeutet, oder
  • - ein Schwefelatom, Sauerstoffatom, oder
  • - eine Gruppe der Formel -NR¹² bedeutet, worin
• R¹² die oben angegebene Bedeutung hat, und
• n und m gleich oder verschieden sind und
  • - eine Zahl 0, 1, 2, 3 oder 4 bedeuten, gefunden.

Substituted fused pyrroles of the general formula (I)

in which

• R '- heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl. Aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or can be substituted by a group of the formula -NR ⁷ R ⁸ , in which
• R ⁷ , R ^{8 - are} identical or different and stand for alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or
• R '- aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl , Trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein
• R7 and R ^{8 have} the meaning given above,
• R ^{2 -} heteroaryl means that up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl. Aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or can be substituted by a group of the formula -NR ⁷ R ⁸ , in which
• R ⁷ , R ^{8 - have} the meaning given above, or
  • - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein
• R ⁷ and R ^{8 have} the meaning given above, or
  • - Cycloalkyl means or
  • - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR'R ⁸ , in which
• R ⁷ , R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals up to the latter 3 -fold the same or different by halogen, cyano, trifluoromethyl, trifluorme thoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl can be substituted,
• _R 3, _R ⁴ , R ⁵ , R ^{6 are the} same or different and
  • - mean hydrogen, or
  • - Cycloalkyl means or
  • - Alkyl, which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR'R ⁸ , in which
• R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are the same or up to 3 may be differently substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or
  • - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein
• R ⁷ and R ^{8 have} the meaning given above, or
  • - Aryl mean that can be substituted up to 5 times by the same or different means by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein
• R ⁷ and R ^{8 have} the meaning given above, or
• R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may optionally be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ , in which
• R ^{9 represents} hydrogen, alkyl, aryl, carbamoyl or alkoxycarbonyl,
• X is a group of the formula -CH ₂ -CH ₂ - or -CH = CH-,
• A - a group of the formula
  
  means what
• R ' ^{o - represents} hydrogen or alkyl, and
• R "- stands for hydrogen, or
  • - represents alkyl, aralkyl or aryl, or
  • - stands for a cation,
• Y - means a bond, or
  • - A group of the formula -NR ' ² means in which
• R ^{12 - represents} hydrogen or alkyl,
• Z - a group of the formula -CH = CH- or -CH ₂ - means, or
  • - a sulfur atom, oxygen atom, or
  • - A group of the formula -NR ¹² means, wherein
• R ^{12 has} the meaning given above, and
• n and m are the same or different and
  • - represent a number 0, 1, 2, 3 or 4, found.

Surprisingly, the substituted fused pyrroles according to the invention show a superior inhibitory effect on the HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme A reductase).

Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. The cyclopropyl, cyclopentane and cyclohexane rings are preferred. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkyl having 1 to about 6 carbon atoms is preferred. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxy radical having 1 to 4 carbon atoms is particularly preferred. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

Alkylthio generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via a sulfur atom. Lower alkylthio having 1 to about 6 carbon atoms is preferred. An alkylthio radical having 1 to 4 carbon atoms is particularly preferred. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Alkylsulfonyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms, which is bonded via an S0 ₂ group. Lower alkylsulfonyl having 1 to about 6 carbon atoms is preferred. Examples include: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl.

Sulfamoyl (aminosulfonyl) stands for the group -SO _Z -NH ₂ .

Aryl generally represents an aromatic radical with 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

Aryloxy generally represents an aromatic radical having 6 to about 12 carbon atoms, which is bonded via an oxygen atom. Preferred aryloxy radicals are phenoxy or naphthyloxy.

Arylthio generally represents an aromatic radical having 6 to about 12 carbon atoms, which is bonded via a sulfur atom. Preferred arylthio radicals are phenylthio or naphthylthio.

Arylsulfonyl generally represents an aromatic radical having 6 to about 12 carbon atoms, which is bonded via an SO _z group. Examples include: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.

Aralkyl generally represents an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain. Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkyl radicals may be mentioned, for example: benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Aralkoxy generally represents an aralkyl radical having 7 to 14 carbon atoms, the alkylene chain being bonded via an oxygen atom. Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkoxy radicals may be mentioned, for example: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.

Aralkylthio generally represents an aralkyl radical having 7 to about 14 carbon atoms, the alkyl chain being bonded via a sulfur atom. Aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples include the following aralkylthio radicals: benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.

Aralkylsulfonyl generally represents an aralkyl radical having 7 to about 14 carbon atoms, the alkyl radicals being bonded via an SO 2 chain. Aralkylsulfonyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkylsulfonyl radicals may be mentioned, for example: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl.

dargestent weraen. Alkyl steht hierbei _Tur einen geradkettgen oaer verzweigten Komenwasserstorrest mit 1 bis 12 Kohlenstoffatomen. Bevorzugt wird Niederalkoxycarbonyl mit 1 bis etwa 6 Kohlenstoffatomen im Alkylteil. Insbesondere bevorzugt wird ein Alkoxycarbonyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil. Beispielsweise seien die folgenden Alkoxycarbonylreste genannt: Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl oder Isobutoxycarbonyl.Alkoxycarbonyl can, for example, by the formula

were shown. Alkyl here represents a _T geradkettgen OAER Komenwasserstorrest branched having 1 to 12 carbon atoms. Lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl part is preferred. An alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part is particularly preferred. Examples include the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Acyl generally represents phenyl or straight-chain or branched lower alkyl having 1 to about 6 carbon atoms which are bonded via a carbonyl group. Phenyl and alkyl radicals having up to 4 carbon atoms are preferred. Examples include: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Halogen generally represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine.

Heteroaryl generally represents a 5- to 6-membered aromatic ring which can contain oxygen, sulfur and / or nitrogen as heteroatoms and to which further aromatic rings can be fused. 5- and 6-membered aromatic rings are preferred which contain an oxygen, a sulfur and / or up to 2 nitrogen atoms and which are optionally benzo-condensed. Particularly preferred heteroaryl radicals may be mentioned: thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolylyloxolylylololylolololylololylololylololylololylololyloloxololylazolylyloxololylazolyloloxololylazolyloloxololylazolyloxazolyloxazolyloxazolyloxazolyloxazolylylazolyloxazolylazolylolazolylazolylazazylylazolylazolylazazolylazazolyl , Indolyl, and isoindolyl.

in welcher

• _R ¹, _R ², _R ³, R⁴, R⁵, R⁶, X, Y, Z, A, n und m die oben angegebene Bedeutung haben.

In the context of the present invention, the substituted fused pyrroles (Ia) correspond to the general formula

in which

• _R ¹ , _R ² , _R ³ , R ⁴ , R ⁵ , R ⁶ , X, Y, Z, A, n and m have the meaning given above.

in welcher

• _R ¹, R², R3, R⁴, R⁵, R⁶, X, Y, Z, A, n und m die oben angegebene Bedeutung haben.

In the context of the present invention, the substituted fused pyrroles (Ib) correspond to the general formula -

in which

• _R ¹ , R ² , R3, R ⁴ , R ⁵ , R ⁶ , X, Y, Z, A, n and m have the meaning given above.

In the context of the general formula (I), compounds having the general formulas (Ia) and (Ib) are preferred.

• R^{I -} Thienyl, Furyl, Thiazolyl, Isothiazolyl, Oxazolyl, Isoxazolyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Indolyl, Isoindolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl, Benzothiazolyl, Benzoxazolyl oder Benzimidazolyl bedeutet, das bis zu 2-fach gleich oder verschieden substituiert sein kann durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy oder Niederalkoxycarbonyl, oder
  • - Phenyl oder Naphthyl bedeutet, das bis zu 4-fach gleich oder verschieden substituiert sein kann durch Niederalkyl, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Phenyl, Phenyloxy, Phenylthio, Phenylsulfonyl, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenethyl, Phenylethoxy, Phenylethylthio, Phenylethylsulfonyl, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluorme thylthio, Niederalkoxycarbonyl oder durch eine Gruppe der Formel -NR⁷R⁸, wobei
• R⁷ und R⁸ gleich oder verschieden sind und für Niederalkyl, Phenyl, Benzyl, Acetyl, Benzoyl, Phenylsulfonyl oder Niederalkylsulfonyl stehen,
• R^{2 -} Thienyl, Furyl, Thiazolyl, Isothiazolyl, Oxazolyl, Isoxazolyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Indolyl, Isoindolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl, Benzothiazolyl, Benzoxazolyl oder Benzimidazolyl bedeutet, das bis zu 2-fach gleich oder verschieden substituiert sein kann durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy oder Niederalkoxycarbonyl, oder
  • - Phenyl oder Naphthyl bedeutet, das bis zu 4-fach gleich oder verschieden substituiert sein kann durch Niederalkyl, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Phenyl, Phenyloxy, Phenylthio, Phenylsulfonyl, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenethyl, Phenylethoxy, Phenylethylthio, Phenylethylsulfonyl, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Niederalkoxycarbonyl oder durch eine Gruppe der Formel -NR'R⁸, wobei
  • R⁷ und R⁸ die oben angegebene Bedeutung haben,
• - oder Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeutet, oder
  • - Niederalkyl bedeutet, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Niederalkoxy, Niederalkylthio. Niederalkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylsulfonyl, Niederalkoxycarbonyl, Benzoyl, Niederalkylcarbonyl, durch eine Gruppe der Formel -NR⁷R⁸, worin
• R⁷ und R⁸ die oben angegebene Bedeutung haben, oder durch Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Chinolyl, Isochinolyl, Pyrrolyl, Indolyl, Thienyl, Furyl, Imidazolyl, Oxazolyl, Thiazolyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenylethoxy, Phenylethylthio oder Phenylethylsulfonyl, wobei die genannten Heteroaryl- und Arylreste bis zu 2-fach gleich oder verschieden durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Trifluormethyl, oder Trifluormethoxy substituiert sein können,
• R3, _R ⁴, R⁵, R⁶ gleich oder verschieden sein können, und
  • - Wasserstoff, oder
  • - Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeuten, oder
  • - Niederalkyl bedeuten, dass substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Trifluormethyl, Trifluormethoxy, Trifluormethylsulfonyl, Niederalkoxycarbonyl, Benzoyl, Niederalkylcarbonyl, durch eine Gruppe der Formel -NR⁷R⁸, worin
• R⁷ und R⁸ die oben angegebene Bedeutung haben, oder durch Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Chinolyl, Isochinolyl, Pyrrolyl, Indolyl, Thienyl, Furyl, Imidazolyl, Oxazolyl, Thiazolyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenylethoxy, Phenylethylthio oder Phenylethylsulfonyl, wobei die genannten Heteroaryl-und Arylreste bis zu 2-fach gleich oder verschieden durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Trifluormethyl, oder Trifluormethoxy substituiert sein können, oder
  • - Thienyl, Furyl, Thiazolyl, Isothiazolyl, Oxazolyl, Isoxazolyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Indolyl, Isoindolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl, Benzothiazolyl, Benzoxazolyl oder Benzimida zolyl bedeuten, das bis zu 2-fach gleich oder verschieden substituiert sein kann durch Fluor, Chlor, Brom, Niederalkyl, Niederalkoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy oder Niederalkoxycarbonyl, oder
  • - Phenyl oder Naphthyl bedeuten, das bis zu 4-fach gleich oder verschieden substituiert sein kann durch Niederalkyl, Niederalkoxy, Niederalkylthio, Niederalkylsulfonyl, Phenyl, Phenyloxy, Phenylthio, Phenylsulfonyl, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl, Phenethyl, Phenylethoxy. Phenylethylthio, Phenylethylsulfonyl, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Niederalkoxycarbonyl oder durch eine Gruppe der Formel -NR⁷R⁸, wobei
• R7 und R⁸ die oben angegebene Bedeutung haben, oder
• R³ und R⁴ und/oder R⁵ und R⁶ jeweils gemeinsam einen Ring bilden, der gegebenenfalls durch ein Sauerstoffatom, ein Schwefelatom oder durch eine Gruppe der Formel -NR⁹ unterbrochen sein kann, worin
• R^{9 -} Wasserstoff, Niederalkyl, Phenyl, Benzyl oder Niederalkoxycarbonyl bedeutet,
• X - eine Gruppe der Formel -CH = CH- bedeutet
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R¹⁰ - für Wasserstoff oder Niederalkyl steht,
• R" - für Wasserstoff steht, oder
  • - für Niederalkyl oder Phenyl steht, oder
  • - für ein physiologisch verträgliches Kation steht, oder
  • - für Benzyl steht,
• Y - eine Bindung bedeutet, oder
  • - eine Gruppe der Formel -NR'² bedeutet, worin
• R'^2-für Wasserstoff oder Niederalkyl steht,
  • Z - eine Gruppe der Formel -CH = CH- oder -CH₂- bedeutet oder
  • - ein Schwefelatom, Sauerstoffatom oder
  • - eine Gruppe der Formel -NR'² bedeutet, worin
• R¹² die oben angegebene Bedeutung hat, und
• n und m gleich oder verschieden sind und
  • eine der aufgeführten Zahlen 0, 1, 2, 3 oder 4 bedeuten.

Compounds of the general formula (I) in which are preferred

• R ^{I -} thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2 may be substituted in the same or different ways by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or
  • - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different manner by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ , in which
• R ⁷ and R ^{8 are the} same or different and represent lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl,
• R ^{2 -} thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2 may be substituted in the same or different ways by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or
  • - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different manner by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR'R ⁸ , where
  • R ⁷ and R ^{8 have} the meaning given above,
• - or cyclopropyl, cyclopentyl or cyclohexyl, or
  • - Lower alkyl means that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio. Lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁷ R ⁸ , wherein
• R ⁷ and R ^{8 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio , Benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, it being possible for the heteroaryl and aryl radicals mentioned to be substituted up to 2 times identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy,
• R3, _R ⁴ , R ⁵ , R ^{6 may be the} same or different, and
  • - hydrogen, or
  • - mean cyclopropyl, cyclopentyl or cyclohexyl, or
  • - Lower alkyl mean that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁷ R ⁸ , in which
• R ⁷ and R ^{8 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio , Benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, where the heteroaryl and aryl radicals mentioned can be substituted up to 2 times identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, or
  • - thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl or benzimazolizolylyl, benzoxazolololyl, benzoxazolololyl, benzoxazolololyl, benzoxazolylolyl, benzoxazolylolyl, benzoxazololol, benzoxazololyl, benzoxazolylol, benzoxazolylol, benzoxazololol may be substituted the same or different by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or
  • - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different ways by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy. Phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ , where
• R7 and R ^{8 have} the meaning given above, or
• R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may optionally be interrupted by an oxygen atom, a sulfur atom or by a group of the formula -NR ⁹ , in which
• R ⁹ denotes hydrogen, lower alkyl, phenyl, benzyl or lower alkoxycarbonyl,
• X - a group of the formula -CH = CH- means
• A - a group of the formula
  
  means what
• R ¹⁰ - represents hydrogen or lower alkyl,
• R "- stands for hydrogen, or
  • - represents lower alkyl or phenyl, or
  • - stands for a physiologically compatible cation, or
  • - stands for benzyl,
• Y - means a bond, or
  • - A group of the formula -NR ' ² , wherein
• R ' ^{2- represents} hydrogen or lower alkyl,
  • Z - a group of the formula -CH = CH- or -CH ₂ - means or
  • - a sulfur atom, oxygen atom or
  • - A group of the formula -NR ' ² , wherein
• R ^{12 has} the meaning given above, and
• n and m are the same or different and
  • one of the numbers 0, 1, 2, 3 or 4 mean.

• R' - Pyridyl, Pyrimidyl, Chinolyl oder Isochinolyl bedeutet, das durch Fluor, Chlor, Methyl, Methoxy oder Trifluormethyl substituiert sein kann, oder
  • - Phenyl bedeutet, das bis zu 3-fach gleich oder verschieden substituiert sein kann durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Phenyl, Phenoxy, Benzyl, Benzyloxy, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl oder tert.Butoxycarbonyl,
• R^{z -} Pyridyl, Pyrimidyl, Chinolyl oder Isochinolyl bedeutet, das durch Fluor, Chlor, Methyl, Methoxy oder Trifluormethyl substituiert sein kann, oder
  • - Phenyl bedeutet, das bis zu 3-fach gleich oder verschieden substituiert sein kann durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Phenyl, Phenoxy, Benzyl, Benzyloxy, Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl oder tert.Butoxycarbonyl, oder
  • - Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeutet, oder
  • - Methyl, Ethyl, Propyl, Isopropyl, Butyl, sec.-Butyl oder tert.Butyl bedeutet, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, sec.Butoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, tert.-Butoxycarbonyl, Benzoyl, Acetyl, Pyridyl, Pyrimidyl, Thienyl, Furyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio oder Benzylsulfonyl,
• R3, _R ⁴, R⁵ und R⁶ gleich oder verschieden sind und
  • - Wasserstoff, Cyclopropyl, Cyclopentyl oder Cyclohexyl bedeuten, oder
  • - Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Pentyl, Isopentyl, Hexyl oder Isohexyl bedeuten, das substituiert sein kann durch Fluor, Chlor, Brom, Cyano, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Butylthio, Isobutylthio, tert.Butylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Butylsulfonyl, Isobutylsulfonyl, tert.Butylsulfonyl, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, tert.Butoxycarbonyl, Benzoyl, Acetyl, Ethylcarbonyl, oder durch eine Gruppe -NR⁷R⁸, wobei
• R⁷ und R⁸ gleich oder verschieden sind und Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Phenyl, Benzyl, Acetyl, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl oder Phenylsulfonyl bedeuten,
  oder durch Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Chinolin, Isochinolyl, Thienyl, Furyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyloxy, Benzylthio oder Benzylsulfonyl, wobei die genannten Heteroaryl-und Arylreste durch Fluor, Chlor, Methyl, Ethyl, Propyl, Isopropyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.-Butoxy, Trifluormethyl oder Trifluormethoxy substituiert sein können, oder
  • - Thienyl, Furyl, Pyridyl, Pyrimidyl, Pyrazinyl, Pyridazinyl, Oxazolyl, Isooxazolyl, Imidazolyl, Pyrazolyl, Thiazolyl. Isothiazolyl, Chinolyl, Isochinolyl, Benzoxazolyl, Benzimidazolyl oder Benzthiazolyl bedeuten, wobei die genannten Reste durch Fluor, Chlor, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Phenyl, Phenoxy, Trifluormethyl, Trifluormethoxy, Methoxycarbonyl, Ethoxycarbonyl, Isopropoxycarbonyl, Propoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl oder tert.Butoxycarbonyl substituiert sein können, oder
  • - Phenyl bedeuten, das bis zu 3-fach gleich oder ver schieden durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Pentyl, Isopentyl, Hexyl, Isohexyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert.Butoxy, Methylthio, Ethylthio, Propylthio, Isopropylthio, Butylthio, Isobutylthio, tert.Butylthio, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Isopropylsulfonyl, Butylsulfonyl, Isobutylsulfonyl, tert.Butylsulfonyl, Phenyl, Phenoxy, Phenylthio, Phenylsulfonyl, Benzyl, Benzyloxy, Benzylthio, Benzylsulfonyl. Fluor, Chlor, Brom, Cyano, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl, tert.Butoxycarbonyl oder durch eine Gruppe -NR⁷R⁸ substituiert sein kann, wobei
• R⁷ und R⁸ die oben angegebene Bedeutung haben, oder
• R³ und R⁴ und/oder R⁵ und R⁶ jeweils gemeinsam einen Ring bilden, der gegebenenfalls durch ein Sauerstoffatom, ein Schwefelatom oder durch eine Gruppe der Formel -NR⁹ unterbrochen sein kann, worin
• R^{9 -} für Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl, tert.Butyl, Phenyl, Benzyl, Methoxycarbonyl, Ethoxycarbonyl, Isopropoxycarbonyl, Propoxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl oder tert.Butoxycarbonyl steht,
• X - eine Gruppe der Formel -CH = CH- bedeutet,
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R'° - für Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl oder tert.Butyl steht,
• R" - für Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl oder Benzyl steht, oder
• - für ein Natrium-, Kalium-, Calcium- oder Magnesium- oder Ammoniumion steht, Y - eine Bindung bedeutet, oder - eine Gruppe der Formel -NR'² bedeutet, worin
• R 12 - für Wasserstoff, Methyl, Ethyl, Propyl, Isopropyl oder tert.Butyl steht, Z - eine Gruppe der Formel -CH = CH- oder -CH₂- bedeutet, oder - ein Schwefelatom, Sauerstoffatom oder eine Gruppe der Formel -NR¹² bedeutet, worin
• R'² die oben angegebene Bedeutung hat, und
• m und n gleich oder verschieden sind und - eine der aufgeführten Zahlen 0, 1, 2, 3 oder 4 bedeuten.

Compounds of the general formula (I) in which are particularly preferred

• R 'is pyridyl, pyrimidyl, quinolyl or isoquinolyl, which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or
  • - Phenyl means that up to 3 times the same or different substitution can be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, butoxycarbonyl, butoxy ,
• R ^z denotes pyridyl, pyrimidyl, quinolyl or isoquinolyl, which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or
  • - Phenyl means that up to 3 times the same or different substitution can be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, butoxycarbonyl, butoxy , or
  • - Cyclopropyl, cyclopentyl or cyclohexyl, or
  • - Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert. Butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, pyridyl, pyridyl, pyridylyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl , Phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl,
• R3, _R ⁴ , R ⁵ and R ^{6 are the} same or different and
  • - mean hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or
  • - Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert.butylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or through a group -NR ⁷ R ⁸ , where
• R ⁷ and R ^{8 are the} same or different and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl,
  or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinoline, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, the heteroaryl and aryl radicals mentioned being fluorine, chlorine, methyl, ethyl, propyl Isopropyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl or trifluoromethoxy may be substituted, or
  • - thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl. Isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, where the radicals mentioned are fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl, or can be substituted
  • - Phenyl mean up to 3 times the same or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.Butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert.Butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio , Benzylsulfonyl. Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or can be substituted by a group -NR ⁷ R ⁸ , where
• R ⁷ and R ^{8 have} the meaning given above, or
• R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may optionally be interrupted by an oxygen atom, a sulfur atom or by a group of the formula -NR ⁹ , in which
• R ^{9 - represents} hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl,
• X means a group of the formula -CH = CH-,
• A - a group of the formula
  
  means what
• R '° - represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl,
• R "- represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or
• - represents a sodium, potassium, calcium or magnesium or ammonium ion, Y - represents a bond, or - represents a group of the formula -NR ' ² , wherein
• R 12 - represents hydrogen, methyl, ethyl, propyl, isopropyl or tert-butyl, Z - represents a group of the formula -CH = CH- or -CH ₂ -, or - a sulfur atom, oxygen atom or a group of the formula -NR ¹² means where
• R ' ^{2 has} the meaning given above, and
• m and n are the same or different and are one of the numbers 0, 1, 2, 3 or 4.

• R' - Phenyl bedeutet, das bis zu 2-fach gleich oder verschieden durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Phenoxy, Benzyloxy, Fluor, Chlor, Brom, Cyano, Trifluormethyl oder Trifluormethoxy substituiert sein kann,
• R^{2 -} Phenyl bedeutet, das bis zu 2-fach gleich oder verschieden durch Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.Butyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Phenoxy, Benzyloxy, Fluor, Chlor, Brom, Cyano, Trifluormethyl oder Trifluormethoxy substituiert sein kann, oder
  • - Cyclopropyl, Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl oder tert.Butyl bedeutet, das durch Fluor, Chlor, Methoxy, Phenyl oder Phenoxy substituiert sein kann,
• R³, R⁴, R^S, R⁶ gleich oder verschieden sind und
  • - Wasserstoff bedeuten, oder
  • - Methyl, Ethyl, Propyl, Isopropyl bedeuten,
• X - eine Gruppe der Formel
  
  bedeutet und
• A - eine Gruppe der Formel
  
  bedeutet, worin
• R¹⁰ - für Wasserstoff steht und
• R¹¹ - für Wasserstoff, Methyl oder Ethyl steht, oder
• - für ein Natrium- oder Kaliumkation steht,
• Y - eine Bindung bedeutet,
• Z - eine Gruppe der Formel -CH_z- bedeutet,
• n - 0 bedeutet und
• m - 1 und 2 bedeutet.

Compounds of the general formulas (Ia) and (Ib) in which are very particularly preferred

• R '- phenyl means up to 2-fold identical or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, benzyloxy, fluorine, chlorine, bromine, Cyano, trifluoromethyl or trifluoromethoxy can be substituted,
• R ^{2 -} phenyl means that up to 2 times the same or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, benzyloxy, fluorine, chlorine, bromine, Cyano, trifluoromethyl or trifluoromethoxy may be substituted, or
  • Means cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, which can be substituted by fluorine, chlorine, methoxy, phenyl or phenoxy,
• R ³ , R ⁴ , R ^S , R ^{6 are the} same or different and
  • - mean hydrogen, or
  • - mean methyl, ethyl, propyl, isopropyl,
• X - a group of the formula
  
  means and
• A - a group of the formula
  
  means what
• R ¹⁰ - stands for hydrogen and
• R ¹¹ - represents hydrogen, methyl or ethyl, or
• - stands for a sodium or potassium cation,
• Y - a bond means
• Z - a group of the formula -CH _z - means
• n - 0 means and
• m means 1 and 2.

The substituted fused pyrroles of the general formula (I) according to the invention have several asymmetric carbon atoms and can therefore exist in various stereochemical formulas. Both the individual isomers and their mixtures are the subject of the invention.

Depending on the meaning of the groups X or the residues A, different stereoisomers result, which will be explained in more detail below:

durch das Symbol

vereinfacht dargestellt.

• a) Steht die Gruppe -X- für eine Gruppe der Formel -CH=CH- , so können die erfindungsgemäßen Verbindungen in zwei stereoisomeren Formen existieren, die an der Doppelbindung E-konfiguriert (II) oder Z-konfigunert (III) sein können:
  
  
  
  und A haben die oben angegebene Bedeutung. Bevorzugt sind diejenigen Verbindungen der allgemeinen Formel (I) die E-konfiguriert sind (II).
• b) Steht der Rest -A- für eine Gruppe der Formel
  
  so besitzen die Verbindungen der allgemeinen Formel (I) mindestens zwei asymmetrische Kohlenstoffatome, nämlich die beiden Kohlenstoffatome an denen die Hydroxygruppen gebunden sind. Je nach der relativen Stellung dieser Hydroxygruppen zueinander, können die erfindungsgemäßen Verbindungen in der erythro-Konfiguration (IV) oder in der threo-Konfiguration (V) vorliegen.
  
  
  Sowohl von den Verbindungen in erythro- als auch in threo-Konfiguration existieren wiederum jeweils zwei Enantiomere, nämlich 3R,5S-Isomeres bzw. 3S,5R-Isomeres (erythro-Form) sowie 3R,5R-Isomeres und 3S,5S-Isomeres (threo-Form). Bevorzugt sind hierbei die erythro-konfigurierten Isomeren, besonders bevorzugt das 3R,5S-Isomere sowie das 3R,5S-3S,5R-Racemat.
• c) Steht der Rest -A für eine Gruppe der Formel
  
  so besitzen die substituierten anellierten Pyrrole mindestens zwei asymmetrische Kohlenstoffatome, nämlich das Kohlenstoffatom an dem die Hydroxygruppe gebunden ist, und das Kohlenstoffatom an welchem der Rest der Formel
  
  gebunden ist. Je nach der Stellung der Hydroxygruppe zur freien Valenz am Lactonring können die substituierten anellierten Pyrrole als cis-Lactone (VI) oder als trans-Lactone (VII) vorliegen.
  
  
  Sowohl vom cis-Lacton aus als auch vom trans-Lacton existieren wiederum jeweils zwei Isomere nämlich das 4R,6R-lsomere bzw. das 4S,6S-Isomere (cis-Lacton), sowie das 4R,6S-Isomere bzw. 4S,6R-Isomere (trans-Lacton). Bevorzugte Isomere sind die trans-Lactone. Besonders bevorzugt ist hierbei das 4R,6S-Isomere (trans) sowie das 4R,6S-4S,6R-Racemat.

In the following explanations, the rest

with the symbol

shown in simplified form.

• a) If the group -X- stands for a group of the formula -CH = CH-, the compounds according to the invention can exist in two stereoisomeric forms which can be E-configured (II) or Z-configured (III) on the double bond:
  
  
  
  and A have the meaning given above. Those compounds of the general formula (I) which are E-configured (II) are preferred.
• b) The rest -A- stands for a group of the formula
  
  the compounds of the general formula (I) have at least two asymmetric carbon atoms, namely the two carbon atoms to which the hydroxyl groups are attached. Depending on the relative position of these hydroxyl groups to one another, the compounds according to the invention can be in the erythro configuration (IV) or in the threo configuration (V).
  
  
  Both of the compounds in erythro and in threo configuration each have two enantiomers, namely 3R, 5S isomer and 3S, 5R isomer (erythro form) as well as 3R, 5R isomer and 3S, 5S isomer ( threo shape). The erythro-configured isomers are preferred, particularly preferably the 3R, 5S isomer and the 3R, 5S-3S, 5R racemate.
• c) The radical -A stands for a group of the formula
  
  so the substituted fused pyrroles have at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is attached and the carbon atom to which the rest of the formula
  
  is bound. Depending on the position of the hydroxyl group in relation to the free valence on the lactone ring, the substituted fused pyrroles can be present as cis-lactones (VI) or as trans-lactones (VII).
  
  
  Both the cis lactone and the trans lactone each have two isomers, namely the 4R, 6R isomer and the 4S, 6S isomer (cis lactone), and the 4R, 6S isomer and 4S, 6R Isomers (trans-lactone). Preferred isomers are the trans lactones. The 4R, 6S isomer (trans) and the 4R, 6S-4S, 6R racemate are particularly preferred.

For example, the following isomeric forms of the substituted fused pyrroles may be mentioned:

In addition, there are further possibilities for isomer formation, since the substituted fused pyrroles according to the invention can contain further centers of chirality. The invention also relates to all stereoisomers which arise from the further chirality centers, in particular in connection with the group -X-A.

in welcher

• R', R², R³, R⁴, R⁵, R⁶, A, X, Y, Z, m und n die oben angegebene Bedeutung haben, gefunden, das dadurch gekennzeichnet ist, daß man Ketone der allgemeinen Formel (VIII)
  
  in welcher
• _R', R², R³, _R ⁴, R^S, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben und
• _R'3 - für Alkyl steht, reduziert,
• und im Fall der Herstellung der Säuren die Ester verseift,
• im Fall der Herstellung der Lactone die Carbonsäuren cyclisiert,
• im Fall der Herstellung der Salze entweder die Ester oder die Lactone verseift,
• im Fall der Herstellung der Ethanverbindung (X = -CH₂-CH₂-) die Ethenverbindung (X = -CH=CH-) nach üblichen Methoden hydriert,
• und gegebenenfalls Isomere trennt.

In addition, a process for the preparation of the substituted fused pyrroles of the general formula (I),

in which

• R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, X, Y, Z, m and n have the meaning given above, which is characterized in that ketones of the general formula (VIII )
  
  in which
• _R ', R ² , R ³ , _R ⁴ , R ^S , R ⁶ , Y, Z, m and n have the meaning given above and
• _R '3 - represents alkyl, reduced,
• and in the case of the production of the acids, the esters are saponified,
• in the case of the production of the lactones, the carboxylic acids are cyclized,
• in the case of the preparation of the salts, either the esters or the lactones are saponified,
• in the case of the preparation of the ethane compound (X = -CH ₂ -CH ₂ -) the ethene compound (X = -CH = CH-) is hydrogenated by customary methods,
• and optionally separates isomers.

The process according to the invention can be illustrated by the following formula:

The reduction can be carried out using the customary reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds. Reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane, is particularly suitable. The reduction is preferably carried out with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkyl hydridoborates, sodium trialkyl hydridoborates, sodium cyano-trihydridoborate or lithium aluminum hydride leads. The reduction with sodium borohydride is very particularly preferably carried out in the presence of triethylborane.

The usual organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane or hydrocarbons such as benzene, toluene or xylene. It is also possible to use mixtures of the solvents mentioned.

The reduction of the ketone group to the hydroxyl group is particularly preferably carried out under conditions in which the other functional groups such as the alkoxycarbonyl group are not changed. The use of sodium borohydride as a reducing agent is particularly suitable for this purpose. in the presence of triethylborane in inert solvents such as preferably ethers.

The reduction generally takes place in a temperature range from -80 ° C. to + 30 ° C., preferably from -78 ° C. to 0 ° C.

The process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).

In general, the reducing agent is used in an amount of 1 to 2 mol, preferably 1 to 1.5 mol, based on 1 mol of the keto compound.

Under the above-mentioned reaction conditions, the carbonyl group is generally reduced to the hydroxyl group without the double bond being reduced to the single bond.

To prepare compounds of the general formula (I) in which X represents an ethylene grouping, the reduction of the ketones (VIII) can be carried out under conditions under which both the carbonyl group and the double bond are reduced.

In addition, it is also possible to carry out the reduction of the carbonyl group and the reduction of the double bond in two separate steps.

in welcher

• _R', R², _R ³, R⁴, R⁵, R⁶, R¹⁰, X, Y, Z, n und m die oben angegebene Bedeutung haben.

The carboxylic acids in the context of the general formula (I) correspond to the formula (Ic)

in which

• _R ', R ² , _R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ , X, Y, Z, n and m have the meaning given above.

in welcher

• R¹, R², R³, R⁴, _R ⁵, R⁶, R¹⁰, X, Y, Z, m und n die oben angegebene Bedeutung haben und
• R'^{3 -} für Alkyl steht.

The carboxylic acid esters in the general formula (I) correspond to the formula (Id)

in which

• R ¹ , R ² , R ³ , R ⁴ , _R ⁵ , R ⁶ , R ¹⁰ , X, Y, Z, m and n have the meaning given above and
• R ' ^{3 - represents} alkyl.

in welcher

• R', R², R³, R⁴, R⁵, R⁶, R¹⁰, X, Y, Z, m und n die oben angegebene Bedeutung haben und
• Ms⊕ für ein Kation steht.

The salts of the compounds according to the invention in the context of the general formula (I) correspond to the formula (Ie)

in which

• R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ , X, Y, Z, m and n have the meaning given above and
• Ms⊕ stands for a cation.

in welcher

• R¹, _R ², R³, R⁴, _R ⁵; R⁶; R¹⁰, X, Y, Z, m und.n die oben angegebene Bedeutung haben.

The lactones in the context of the general formula (I) correspond to the formula (If)

in which

• R ¹ , _R ² , R ³ , R ⁴ , _R ⁵ ; R ⁶ ; R ¹⁰ , X, Y, Z, m and.n have the meaning given above.

To prepare the carboxylic acids of the general formula (Ic) according to the invention, the carboxylic acid esters of the general formula (Id) or the lactones of the general formula (If) are in general saponified by customary methods. The saponification is generally carried out by treating the esters or the lactones in inert solvents with customary bases, the salts of the general formula (Ie) generally being formed first, which are then, in a second step, treated with acid in the free acids of the general Formula (Ic) can be transferred.

The usual inorganic bases are suitable as bases for the saponification. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali metal alcoholates such as sodium ethanolate, sodium methoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide. Sodium hydroxide or potassium hydroxide are particularly preferably used.

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.

The saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from + 20 ° C. to + 80 ° C.

The saponification is generally carried out at normal pressure. However, it is also possible to work under negative pressure or overpressure (e.g. from 0.5 to 5 bar).

When saponification is carried out, the base is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the ester or lactone. Molar amounts of the reactants are particularly preferably used.

When the reaction is carried out, the salts of the compounds (Ie) according to the invention are formed in the first step as intermediates which can be isolated. The acids (Ic) according to the invention are obtained by treating the salts (le) with customary inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or Phosphoric acid. In the production of the carboxylic acids (Ic), it has proven advantageous here to acidify the basic reaction mixture of the saponification in a second step without isolating the salts. The acids can then be isolated in the usual way.

To produce the lactones of the formula (If) according to the invention, the carboxylic acids (Ic) according to the invention are generally cyclized by customary methods, for example by heating the corresponding acid in inert organic solvents, if appropriate in the presence of molecular sieve.

Suitable solvents here are hydrocarbons such as benzene, toluene, xylene, petroleum fractions, or tetralin or diglyme or triglyme. Benzene, toluene or xylene are preferably used. It is also possible to use mixtures of the solvents mentioned. Hydrocarbons, in particular toluene, are particularly preferably used in the presence of molecular sieve.

The cyclization is generally carried out in a temperature range from -40 ° C. to + 200 ° C., preferably from -25 ° C. to + 50 ° C.

The cyclization is generally carried out at normal pressure, but it is also possible to carry out the process under reduced pressure or under elevated pressure (e.g. in a range from 0.5 to 5 bar).

In addition, the cyclization is also carried out in inert organic solvents with the aid of cyclizing or water-releasing agents. Carbodiimides are preferably used as water-releasing agents. N, N -dicyclohexylcarbodiimide paratoluenesulfonate, N-cyclohexyl-N '- [2- (N "-methylmorpholinium) ethyl] carbodilmide or N- (3-dimethyiamino-propyl) -N-ethylcarbodiimide hydrochloride are preferably used as carbodiimides.

The usual organic solvents are suitable as solvents. These preferably include ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions. Chlorinated hydrocarbons such as, for example, methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene, or petroleum fractions are particularly preferred. Chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride are particularly preferably used.

The reaction is generally carried out in a temperature range from 0 ° C. to + 80 ° C., preferably from + 10 ° C. to + 50 ° C.

When carrying out the cyclization, it has proven to be advantageous to use the cyclization method with the aid of carbodiimides as dehydrating agents.

in welcher

• _R', _R ², _R3, R⁴, R⁵, R⁶, X, Y, Z, m und n die oben angegebene Bedeutung haben,
• überführt, die anschließend wie üblich durch Chromatographie oder Kristallisation in die einzelnen Diastereomerens getrennt werden können. Anschließend Hydrolyse der reinen diastereomeren Amide nach üblichen Methoden, beispielsweise durch Behandeln der diastereomeren Amide mit anorganischen Basen wie Natriumhydroxid oder Kaliumhydroxid in Wasser und/oder organischen Lösemitteln wie Alkoholen z.B. Methanol, Ethanol, Propanol oder Isopropanol, ergeben die entsprechenden enantiomerenreinen Dihydroxysäuren (Ic), die wie oben beschrieben durch Cyclisierung in die enantiomerenreinen Lactone überführt werden können.

The separation of the isomers into the stereoisomerically uniform constituents is generally carried out by customary methods as described, for example, by EL Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962. The separation of the isomers at the racemic ester stage is preferred. The racemic mixture of the trans-lactones (VII) is particularly preferred here by treatment with either D - (+) - or L - (-) - a-methylbenzylamine by customary methods into the diastereomeric dihydroxyamides (Ig)

in which

• _{R '} , _R ² , _R 3, R ⁴ , R ⁵ , R ⁶ , X, Y, Z, m and n have the meaning given above,
• transferred, which can then be separated into the individual diastereomers as usual by chromatography or crystallization. Subsequent hydrolysis of the pure diastereomeric amides by customary methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium hydroxide in water and / or organic solvents such as alcohols, for example methanol, ethanol, propanol or isopropanol, give the corresponding enantiomerically pure dihydroxy acids (Ic), which are converted into the enantiomerically pure lactones by cyclization as described above can be.

In general, it applies to the preparation of the compounds of the general formula (I) according to the invention in enantiomerically pure form that the configuration of the end products by the method described above depends on the configuration of the starting materials.

The separation of isomers is to be exemplified in the following scheme:

The ketones (VIII) used as starting materials are new.

in welcher

• _R'. R², _R3. R⁴, _R ⁵, R⁶, R¹³, Y, Z, m und n die oben angegebene Bedeutung haben, gefunden, das dadurch gekennzeichnet ist, daß man
• Aldehyde der allgemeinen Formel (IX)
  
  in welcher
• R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben, in inerten Lösemitteln mit Acetessigestern der allgemeinen Formel (X)
  
  in welcher
• R'³ die oben angegebene Bedeutung hat,
• in Anwesenheit von Basen umsetzt.

A process for the preparation of the ketones of the general formula (VIII) according to the invention

in which

• _R '. R ² , _R 3. R ⁴ , _R ⁵ , R ⁶ , R ¹³ , Y, Z, m and n have the meaning given above, which is characterized in that
• Aldehydes of the general formula (IX)
  
  in which
• R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Z, m and n have the meaning given above, in inert solvents with acetoacetic esters of the general formula (X)
  
  in which
• R ' ^{3 has} the meaning given above,
• in the presence of bases.

The method according to the invention can be illustrated, for example, by the following formula:

The bases here are the customary strongly basic compounds. These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenylli thium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethyldisilylamide, or alkali hydrides such as sodium hydride or potassium hydride. It is also possible to use mixtures of the bases mentioned. N-Butyllithium or sodium hydride or a mixture thereof is particularly preferably used.

The usual organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or hydrocarbons such as benzene, toluene, xylene, cyclohexane, hexane or oil fractions. It is also possible to use mixtures of the solvents mentioned. Ethers such as diethyl ether or tetrahydrofuran are particularly preferably used.

The reaction is generally carried out in a temperature range from -80.degree. C. to + 50.degree. C., preferably from -20.degree. C. to + 30.degree.

The process is generally carried out at normal pressure, but it is also possible Carry out the process under reduced pressure or overpressure, for example in a range from 0.5 to 5 bar.

When carrying out the process, the acetoacetic ester is generally used in an amount of 1 to 2, preferably 1 to 1.5, mol, based on 1 mol of the aldehyde.

The acetoacetic esters of the formula (X) used as starting materials are known or can be prepared by known methods [Beilstein's Handbuch der organic Chemistry 111, 632; 438].

• Acetessigsäureethylester,
• Acetessigsäurepropylester,
• Acetessigsäueisopropylester.

Examples of acetoacetic esters for the process according to the invention are: methyl acetoacetate,

• Ethyl acetoacetate,
• Acetoacetic acid propyl ester,
• Isopropyl acetoacetate.

The aldehydes of the general formula (IX) used as starting materials are new.

in welcher

• R¹, R², R³, R⁴, R^S, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben, gefunden, das dadurch gekennzeichnet ist, daß man
• substituierte Pyrrole der allgemeinen Formel (XI)
  
  in welcher
• R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben,
• in inerten Lösemitteln in Anwesenheit von Hilfsstoffen mit N,N-Dialkylaminoacrolein der Formel (XII)
  
  wobei
• Alkyl- für einen geradkettigen oder verzweigten Kohlenwasserstoffrest mit 1 bis 6 Kohlenstoffatomen steht, umsetzt.

A process for the preparation of the aldehydes of the general formula (IX)

in which

• R ¹ , R ² , R ³ , R ⁴ , R ^S , R ⁶ , Y, Z, m and n have the meaning given above, which is characterized in that
• substituted pyrroles of the general formula (XI)
  
  in which
• R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Z, m and n have the meaning given above,
• in inert solvents in the presence of auxiliaries with N, N-dialkylaminoacrolein of the formula (XII)
  
  in which
• Alkyl is a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms.

The method according to the invention can be illustrated, for example, by the following formula:

Suitable solvents here are the customary organic solvents which are stable under the reaction conditions. These preferably include hydrocarbons such as benzene, toluene, xylene, hexane, petroleum fractions, chlorobenzene or dichlorobenzene, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Anhydrous acetonitrile or chloroform is particularly preferably used.

Acid chlorides are generally used as auxiliaries. Phosphorus oxychloride or phosgene is preferably used, particularly preferably phosphorus oxychloride.

The reaction is carried out in a temperature range from -20 ° C to + 150 ° C, preferably from 0 ° C to + 100 ° C.

The process is generally carried out at normal pressure. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).

When carrying out the process, the dimethylaminoacrolein is generally used in an amount of 1 to 6, preferably 1 to 2, mol, based on 1 mol of the pyrrole.

The substituted fused pyrroles of the general formula (XI) used as starting materials are known per se (J. Med. Chem. 1987, 30, 820-823).

in welcher

• _R', _R ², R³, R⁴, _R ⁵, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben, gefunden das dadurch gekennzeichnet ist, daß man
• Diketone der allgemeinen Formel (XIII), (XIV), (XV) und (XVI)
  
  
  
  
  in welchen
• R¹, _R ², _R3, R⁴, R⁵, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben, und
• R¹⁴ und R¹⁵ gleich oder verschieden sind und
• - die für primäre Amine üblichen Schutzgruppen wie Acyl, Phthalimido, Benzyl oder tert.Butoxycarbonyl bedeuten,
• in organischen Lösemitteln in Anwesenheit von Hilfsstoffen wie Wasserstoff, Hydrierkatalysatoren, Säuren und Wasser, zu Aminodiketonen der allgemeinen Formel (XVII) und (XVIII)
  
  
  in welchen
• R¹, R², R³, R⁴, R^S, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben, umsetzt, die unter den Reaktionsbedingungen zu den substituierten anellierten Pyrrolen (XI) cyclisieren.

A process for the preparation of the substituted fused pyrroles of the general formula (XI)

in which

• _R ', _R ² , R ³ , R ⁴ , _R ⁵ , R ⁶ , Y, Z, m and n have the meaning given above, found that is characterized in that
• Diketones of the general formula (XIII), (XIV), (XV) and (XVI)
  
  
  
  
  in which
• R ¹ , _R ² , _R 3, R ⁴ , R ⁵ , R ⁶ , Y, Z, m and n have the meaning given above, and
• R ¹⁴ and R ^{15 are the} same or different and
• the protective groups customary for primary amines, such as acyl, phthalimido, benzyl or tert-butoxycarbonyl,
• in organic solvents in the presence of auxiliaries such as hydrogen, hydrogenation catalysts, acids and water, to aminodiketones of the general formulas (XVII) and (XVIII)
  
  
  in which
• R ¹ , R ² , R ³ , R ⁴ , R ^S , R ⁶ , Y, Z, m and n have the meaning given above, which cyclize under the reaction conditions to the substituted fused pyrroles (XI).

Suitable solvents here are the customary organic solvents which are stable under the reaction conditions. These preferably include hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, petroleum fractions, or ethers such as diethyl ether, dioxane, tetrahydrofuran or alcohols such as methanol, ethanol or propanol. It is also possible to use mixtures of the solvents mentioned. Methanol or ethanol is particularly preferably used.

Hydrogen and hydrogenation catalysts are generally used as auxiliaries. Raney cobalt and hydrogen are preferably used.

The reaction is carried out in a temperature range from -20 ° C to + 250 ° C, preferably from 0 ° C to + 100 ° C.

The process is generally carried out under pressure. The range from 1 to 300 bar is preferred, particularly preferably the range from 20 to 80 bar.

Some of the diketones of the general formula (XIII), (XIV), (XV) and (XVI) used as starting materials are new or can be prepared by known methods [Angew. Chemie, 88, 695 796 (1976)].

In the event that R ^{3 is} different from R ⁴ and / or R ^{5 has} a different meaning than R ⁶ , further stereoisomers can occur.

in welcher

• _R', _R ², R³, _R ⁴, _R ⁵, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben,
• in stereoisomer einheitliche Bestandteile nach üblichen Methoden, wie sie beispielsweise von E.L. Eliel, Stereochemistry of Carbon Compounds, Mc Graw Hill, 1962 beschrieben werden, trennt.

Enantiomerically pure forms of the general formula (IX) are obtained, for example, by mixing diastereomer mixtures of the compounds of the general formula (IXX)

in which

• _{R '} , _R ² , R ³ , _R ⁴ , _R ⁵ , R ⁶ , Y, Z, m and n have the meaning given above,
• into stereoisomerically uniform constituents by conventional methods, as described, for example, by EL Eliel, Stereochemistry of Carbon Compounds, Mc Graw Hill, 1962.

in welcher

• R¹, R², R³, R⁴, R^S, R⁶, Y, Z, m und n die oben angegebene Bedeutung haben, hergestellt werden.

The separation can take place, for example, via salts or amides with chiral bases. By subsequent chromatography or crystallization, the enantiomerically pure carboxylic acids of the general formula (IXXa), (IXXb), (IXXc) and (IXXd)

in which

• R ¹ , R ² , R ³ , R ⁴ , R ^S , R ⁶ , Y, Z, m and n have the meaning given above, are prepared.

According to conventional methods, the compounds of the general formulas (IXXa), (IXXb), (IXXc) and (IXXd) are first reduced to alcohol, oxidized and then subjected to formyl olefinization with phosphonic acid [2- (cyclohexylamino) vinyl] diethyl ester.

Some of the compounds of the general formula (IXX) are known or new and can be prepared from the compounds of the general formula (XI) by a customary method [C. Ferri, Reactions in Organic Synthesis, Georg Thieme Verlag, Stuttgart, 1978].

Chiral bases can be used to separate the diastereomer mixture of the general formula (IXX). Quinine, cinchonine, cinchonidine, brucine, D - (+) - or L - (-) - a-methyl-benzylamine are preferred.

Lithium aluminum hydride is used to reduce the compounds of the general formulas (IXXa), (IXXb), (IXXc) and (IXXd)
or diisobutyl aluminum hydride used. Diisobutyl aluminum hydride is preferred.

The oxidation takes place according to the usual method [cf. C. Ferri, Reactions in Organic Synthesis, Georg Thieme Verlag, Stuttgart, 1978]. Pyridinium chlorochromate is preferably used.

Phosphonic acid [2- (cyclohexylamino) vinyl] diethyl ester is known [Tetrahedron Lett. 1968, (41), 4359-4362].

The production process for the enantiomerically pure forms according to the invention can be illustrated by the following reaction schemes:

The compounds of general formula (I) according to the invention can be active ingredients for medicinal products. In particular, they are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HGM-CoA) reductase and consequently inhibitors of cholesterol biosynthesis. They can therefore be used to treat hyperlipoproteinemia, lipoproteinemia or arteriosclerosis.

The new active ingredients can be converted into the customary formulations in a known manner, such as Tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 98% by weight, preferably 1 to 90% by weight, of the total mixture, that is to say in amounts which are sufficient to give the stated dosage range to reach.

The formulations are prepared, for example, by stretching the active ingredients with solvents and or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

Examples of auxiliaries include: water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut sesame oil), alcohols (e.g. ethyl alcohol, glycerol), carriers such as e.g. natural stone flours (e.g. kaolins, clays, talc, chalk), synthetic stone flours (e.g. highly disperse silica, silicates), sugar (e.g. cane, milk and dextrose), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, Alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin sulfite waste liquors, methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in the usual way, preferably orally, parenterally, perlingually or intravenously. In the case of oral use, tablets can of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like, in addition to the carrier substances mentioned. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active ingredients can be mixed with various flavor enhancers or colorants.

In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials.

In general, it has been found to be advantageous to administer amounts of about 0.001 to 1 mg _/ kg, preferably about 0.01 to 0.5 mg, kg of body weight in the case of intravenous administration in order to achieve effective results, and the dosage is for oral administration about 0.01 to 20 mg, kg, preferably 0.1 to 10 mg, of body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the drug, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses over the day.

Manufacturing examples example 1 (E) -4,4-Dimethyl-7- (4-fluorophenyl) -5-oxo-hept-6-enenitrile

• Ausbeute: 117 g (48% der Theorie)
• Fp.: 68 - 69 C
• 1H-NMR (CDCI₃): δ- 1,3 (s, 6H, CH₃); 2,0 (t, 2H, CH₂-CH₂-CN); 2,3 (t, 2H, CH₂-CN); 7,0 (d, J = 15 Hz, 1H, Olefin-H); 7,0 - 7,2 (m, 2H, Aryl-H); 7,5 - 7,7 (m, 2H,Aryl-H); 7,7 ppm (d, J = 15 Hz, Olefin-H).

To a suspension of 124 g (1 mol) of 4-fluorobenzaldehyde and 139 g (1 mol) of 4,4-dimethyl-5-oxohexanoic acid nitrile [LB Barkley, RL Levine, J. Am. Chem. Soc. 72, 3699 - 701 (1950)] in 1000 ml of water, 120 ml of 10% sodium hydroxide solution are added and the mixture is stirred for 60 hours in a room te temperature. The pH is adjusted to 5-7 with acetic acid. The organic phase is separated off and unreacted starting material is distilled off in vacuo, which is used again in the reaction and worked up in the same way. The residues from the distillation are filtered through silica gel with methylene chloride. After concentration, the residue crystallizes. The crude product is recrystallized from ethanol.

• Yield: 117 g (48% of theory)
• Mp .: 68-69 C.
• 1H NMR (CDCI ₃ ): δ- 1.3 (s, 6H, CH ₃ ); 2.0 (t, 2H, CH ₂ -CH ₂ -CN); 2.3 (t, 2H, CH ₂ -CN); 7.0 (d, J = 15 Hz, 1H, olefin-H); 7.0 - 7.2 (m, 2H, aryl-H); 7.5 - 7.7 (m, 2nd H, Aryl-H); 7.7 ppm (d, J = 15 Hz, olefin-H).

Example 2 4,4-dimethyl-5,8-dioxo-7- (4-fluorophenyl) -8-phenyl-octanoic acid nitrile

• Ausbeute: 115,3 g (73% der Theorie) gelbes Öl
• ¹H-NMR (CDCI₃): δ = 1,14 und 1,22 (2s, 6H, CH₃); 1,8 -2,0 (m, 2H, CH₂-CH₂-CN); 2,15 - 2,30 (m, 2H, CH₂-CN); 2,76 (dd, 1H, CO-CH-CH₂-CO); 3,60 (dd, 1H, CO-CH-CH₂-CO); 5,12 (dd, 1H, CO-CH-CH₂-CO); 6,9 - 7,0 (m, 2H, Aryl-H); 7,2 - 7,5 (m, 5H, Aryl-H); 7,95 ppm (m, 2H, Aryl-H).

A solution of 63.6 g (0.6 mol) of benzaldehyde in 250 ml of dimethylformamide is added dropwise at 35 ° C. to a solution of 5.9 g (0.12 mol) of sodium cyanide in 250 ml of dimethylformamide. A solution of 110.3 g (0.45 mol) of (E) -4,4-dimethyl-7- (4-fluorophenyl) -5-oxo-hept-6-enenonitrile (Example 1) in 250 ml is then added dropwise Dimethylformamide and stirred for 12 h at room temperature. After adding 1 l of water, the mixture is extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. Residual dimethylformamide is removed by distillation in a high vacuum. The residue is filtered through silica gel with methylene chloride and concentrated.

• Yield: 115.3 g (73% of theory) of a yellow oil
• ¹ H NMR (CDCI ₃ ): δ = 1.14 and 1.22 (2s, 6H, CH ₃ ); 1.8 -2.0 (m, 2H, CH ₂ -CH ₂ -CN); 2.15 - 2.30 (m, 2H, CH ₂ -CN); 2.76 (dd, 1H, CO-CH-CH ₂ -CO); 3.60 (dd, 1H, CO-CH-CH ₂ -CO); 5.12 (dd, 1H, CO-CH-CH ₂ -CO); 6.9 - 7.0 (m, 2H, aryl-H); 7.2 - 7.5 ( m, 5H, aryl-H); 7.95 ppm (m, 2 H , Aryl-H).

Example 3 8,8-dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydroindolizine

• Ausbeute: 61,6 g (62% der Theorie)
• Fp.: 141 - 142° C
• ¹H-NMR (CDCl₃): δ = 1,38 (s, 6H, CH₃); 1,70 (m, 2H, CH₂-C(CH₃)₂); 1,95 (m, 2H, N-CH₂-CH_z); 3,70 (t, 2H, N-CH₂); 6,17 (s, 1H, Pyrrol-H); 6,75 - 6,90 (m, 2H, Aryl-H); 7,05 - 7,15 (m, 2H, Aryl-H); 7,25- 7,40 ppm (m, 5H, Aryl-H).

109 g (0.31 mol) of 4,4-dimethyl-5,8-dioxo-7- (4-fluorophenyl) -8-phenyl-octanoic acid nitrile (Example 2) are dissolved in 1.2 l of methanol in the presence of 15 g of Raney -Carbon hydrogenated at a temperature of 80 - 90 ° C under a pressure of 50 - 60 bar hydrogen until the end of the hydrogen uptake. The precipitated crystals are dissolved by adding acetone. After filtering off the catalyst, the mixture is concentrated and the residue is recrystallized from ethanol.

• Yield: 61.6 g (62% of theory)
• Mp: 141-142 ° C
• ¹ H NMR (CDCl ₃ ): δ = 1.38 (s, 6H, CH ₃ ); 1.70 (m, 2H, CH ₂ -C (CH ₃ ) ₂ ); 1.95 (m, 2H, N-CH ₂ -CH _z); 3.70 (t, 2H, _N-CH2); 6.17 (s, 1H, pyrrole-H); 6.75 - 6.90 (m, 2H, aryl -H ); 7.05 - 7.15 (m, 2H, aryl-H); 7.2 5- 7.40 ppm (m, 5H, aryl-H).

Example 4 (E) -3- [8,8-Dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydroindolizin-1-yl] prop-2-enal

• Ausbeute: 13,7 g (61% der Theorie)
• Fp.: 182 - 183° C
• 'H-NMR (CDCI₃); δ = 1,58 (s, 6H, CH₃); 1,75 - 1,85 (m, 2H, CH₂-C(CH₃)₂); 1,85 - 2,00 (m, 2H, N-CH_z-CH_z); 3,72 (t, 2H, N-CH₂); 5,63 (dd, 1 H, Olefin-H); 6,80 - 6,95 (m, 2H, Aryl-H); 7,00 - 7,30 (m, 7H, Aryl-H); 7,80 (d, 1 H, Olefin-H); 9,38 ppm (d, 1 H, CHO).

9.8 g (90 mmol) of 90% dimethylaminoacrolein in 50 ml of acetonitrile are added dropwise under nitrogen at -10 ° C. to a solution of 13.8 g (90 mmol) of phosphorus oxychloride in 200 ml of anhydrous acetonitrile. 19.15 g (60 mmol) of 8,8-dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydroindolizine (Example 3) are added at 0 ° C. The mixture is allowed to come to room temperature and then stirred for 24 hours at 40 ° C. The batch is then added at 10 ° C. to a suspension of 22 g of sodium hydroxide in 450 ml of water and 450 ml of toluene. After stirring for 1 h, the toluene phase is separated off. After washing with water, drying over sodium sulfate and concentration, the product is recrystallized from ethanol.

• Yield: 13.7 g (61% of theory)
• Mp: 182-183 ° C
• 'H NMR (CDCI ₃ ); δ = 1.58 (s, 6H, CH ₃ ); 1.75 - 1.85 (m, 2H, CH ₂ -C (CH ₃ ) ₂ ); 1.85 - 2.00 (m, 2H, N-CH _z -CH _z ); 3.72 (t, 2H, _N-CH2); 5.63 (dd, 1H, olefin-H); 6.80 - 6.95 (m, 2H, Aryl-H); 7.00 - 7.30 (m, 7H, aryl-H); 7, 80 (d, 1H, olefin-H); 9.38 ppm (d, 1H, CHO).

Example 5 Methyl- (E) -7- [8,8-dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydroindolizin-1-yl] -5-hydroxy-3-oxo hept-6-enoate

• R_f = 0,28
• 'H-NMR (DMSO): δ = 1,38 (s, 6H, CH₃); 1,65 - 1,75 (m, 2H, CH₂-C(CH₃)₂); 1,75 - 1,90 (m, 2H, N-CH₂-CH₂); 2.40 (m, 2H, CH(OH)-CH₂); 3,60 (s, 3H, COOCH₃); 3,65 (m, 2H, N-CH_z); 4,35 (m, 1H, CH(OH); 4,85 (d, 1 H, CH-COOCH₃ (Enolform)); 4,90 (dd, 1 H, Olefin-H); 6,65 (d, 1 H, Olefin-H); 6,9 - 7,3 ppm (m, 9H, Aryl-H).

Under nitrogen, dropwise to a suspension of 0.96 g (32 mmoi) of 80% sodium hydride in 50 ml of anhydrous tetrahydrofuran at 0 ° C 3.0 g (30 mmol) of methyl acetoacetate in 20 ml of tetrahydrofuran. After 15 min, 14.4 ml (36 mmol) of a 2.5 molar solution of n-butyllithium in hexane are added dropwise at the same temperature. After 15 minutes, 7.46 g (20 mmol) of (E) -3- [8,8-dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydroindolizine- 1-yl] -prop-2-enal (Example 4) dissolved in 100 ml of tetrahydrofuran was added dropwise. After 15 minutes, 4 g of glacial acetic acid are added dropwise in 40 ml of water. The mixture is poured onto ice water and, after the organic phase has been separated off, extracted twice with ether. The combined organic phases are washed twice with sodium hydrogen carbonate solution and twice with saturated sodium chloride solution. After drying over sodium sulfate and concentration, chromatographed and with cyclohexane / acetone (2: 1) on 250 g of silica gel (70-230 mesh). Yield: 8.9 g (91% of theory) of reddish oil

• R _f = 0.28
• 'H NMR (DMSO): δ = 1.38 (s, 6H, CH ₃ ); 1.65 - 1.75 (m, 2H, CH ₂ -C (CH ₃ ) ₂ ); 1.75 to 1.90 (m, 2H, N-CH ₂ -CH _2); 2:40 (m, 2H, CH (OH) -CH _2); 3.60 (s, 3H, COOCH ₃ ); 3.65 (m, 2H, N-CH _z ); 4.35 (m, 1H, CH (OH); 4.85 (d, 1 H, CH-COOCH ₃ (Enolfor m) ); 4.90 (dd, 1H, olefin-H); 6.65 (d, 1H, olefin-H); 6.9 - 7.3 ppm (m , 9H, aryl-H).

Example 6 Methyl erythro- (E) -3,5-dihydroxy-7- [8,8-dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydroindolizin-1-yl] - hept-6-enoate

• R_f = 0,20
• ¹H-NMR (DMSO): δ = 1,38 (s, 6H, CH₃); 1,65 - 1,75 (m, 2H, CH₂-C(CH₃)₂); 1,75 - 1,90 (m, 2H, N-CH₂-CH₂); 2,20 - 2,45 (2 dd, 2H, CH_z-COOCH₃); 3,55 (s, 3H, COOCH₃ ); 3,65 (m, 2H, N-CH₂); 3,80 und 4,05 (2m, 2H, CH(OH)); 4,88 (dd, 1 H, Olefin-H); 6,60 (d, 1 H, Olefin-H); 6,9 - 7,3 ppm (m, 9H, Aryl-H).

Under nitrogen, dropwise to a solution of 4.89 g (10 mmol) of methyl- (E) -7- [8,8-dimethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8 -tetrahydroindolizin-1-yl] -5-hydroxy-3-oxo-hept-6-enoate (Example 5) in 50 ml of anhydrous tetrahydrofuran to 12 ml (12 mmol) of a 1 molar solution of triethylborane in hexane at room temperature, while conducts 5 min air through the solution and then cools down to -80 ° C. 0.45 g (12 mmol) of sodium borohydride are added, and 6.7 ml of methanol are slowly added dropwise, and the mixture is stirred at -75 ° C. for 15 min and at -30 ° C. for 15 min. A solution of 32.5 ml of 30% hydrogen peroxide in 65 ml of water is then added dropwise. In the course of the addition, the temperature is allowed to rise to room temperature. After phase separation, the mixture is extracted with ethyl acetate. The combined organic phases are washed twice with sodium hydrogen carbonate solution and twice with saturated sodium chloride solution. After drying over sodium sulfate and concentration, the mixture is chromatographed on 250 g of silica gel (35-70 μm) using cyclohexane / acetone (2: 1). Yield: 3.5 g (71% of theory) of an amorphous solid

• R _f = 0.20
• ¹ H NMR (DMSO): δ = 1.38 (s, 6H, CH ₃ ); 1.65 - 1.75 (m, 2H, CH ₂ -C (CH ₃ ) ₂ ); 1.75 to 1.90 (m, 2H, N-CH ₂ -CH _2); 2.20 - 2.45 (2 dd, 2H, CH _z -COOCH ₃ ); 3.55 (s, 3H, COOCH _3rd ); 3.65 (m, 2H, _N-CH2); 3.80 and 4.05 (2m, 2H, CH (OH)); 4.88 (dd, 1H, O lef in-H); 6.60 (d, 1H, olefin-H); 6.9-7.3 ppm (m, 9H, aryl-H).

Example 7 (E) -7- (4-fluorophenyl) -5-oxo-4- (2-propyl) -hept-6-enenitrile

• 'H-NMR (CDCl₃): δ = 0,90 und 1,01 (2d, 6H, CH₃); 1,8 (m, 1H, CH(CH₃)₂; 2,0 - 2,5 (m, 4H, CH₂-CH₂-CN); 2,85 (m, 1 H, CO-CH); 6,77 (d, J = 15 Hz, 1H. Olefin-H); 7,0 - 7,2(m, 2H, Aryl-H); 7,5 - 7,7 ppm (m, 3H, 2 Aryl-H und 1 Olefin-H).

To a solution of 4.2 g (0.105 mol) of sodium hydroxide in 100 ml of water is added a solution of 34.9 g (0.228 mol) of 5-oxo-4- (2-propyl) -hexanoic acid nitrile [G. Näslund, A. Senning, SO Lawesson; Acta Chem. Scand. 16. 1324-8 (1962)] and 28.3 g (0.228 mol) of 4-fluorobenzaldehyde in 400 ml of methanol and stirred for 96 h at room temperature. After concentration, water is added, the mixture is extracted with methylene chloride, dried over sodium sulfate and concentrated. The residue is filtered through silica gel with methylene chloride. Yield: 31.7 g (54% of theory)

• 'H NMR (CDCl ₃ ): δ = 0.90 and 1.01 (2d, 6H, CH ₃ ); 1.8 (m, 1H, CH (CH ₃ ) ₂ ; 2.0-2.5 (m, 4H, CH ₂ -CH ₂ -CN); 2.85 (m, 1 H, CO-CH); 6.77 (d, J = 15 Hz, 1H. Olefin-H); 7.0 - 7, 2 ( m, 2H, aryl-H); 7.5-7.7 ppm (m, 3H, 2 aryl-H and 1 olefin-H).

Example 8 5,8-dioxo-7- (4-fluorophenyl) -8-phenyl-4- (2-propyl) octanoic acid nitrile

• Ausbeute: 33.2 g (76% der Theorie) gelbes ÖI.
• 'H-NMR (CDCl₃): δ = 0,80; 0.88; 0,94 und 1,01 (4d, 6H, CH₃); 1,60 - 1,85 (m, 1 H, CH(CH₃)₂); 1,85 - 2,45 (m, 4H, CH₂-CH₂-CN); 2,45 - 2,75 (2m, 1H, CO-CH-CH₂-CH₂-CN); 2,65 - 2,90 (m, 1H, CH₂-CO); 3,50 und 3,72 (2dd, 1 H, CH₂-CO); 5,12 (dd, 1 H, CO-CH-CH ₂ -CO); 6,95 (m, 2H, Aryl-H); 7,15 - 7,60 (m, 5H, Aryl-H): 7,95 ppm (m, 2H, Aryl-H).

A solution of 17.0 g (0.16 mol) of benzaldehyde in 65 ml of dimethylformamide is added dropwise to a solution of 1.5 g (0.031 mol) of sodium cyanide in 65 ml of dimethylformamide at 35 ^° C. A solution of 31.1 g (0.12 mol) of (E) -7- (4-fluorophenyl) -5-oxo-4- (2-propyl) -hept-6-enenonitrile (Example 7) is then added dropwise 65 ml of dimethylformamide and stirred for 12 h at room temperature. After adding 250 ml of water, the mixture is extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. Residual dimethylformamide is removed by distillation in a high vacuum. The residue is filtered through silica gel with methylene chloride and concentrated.

• Yield: 33.2 g (76% of theory) of yellow oil.
• 'H NMR (CDCl ₃ ): δ = 0.80; 0.88; 0.94 and 1.01 (4d, 6H, CH ₃ ); 1.60 to 1.85 (m, 1 H, CH (CH _{3) 2);} 1.85 - 2.45 (m, 4H, CH ₂ -CH ₂ -CN); 2.45 - 2.75 (2m, 1H, CO-CH-CH ₂ -CH ₂ -CN); 2.65 - 2.90 (m, 1st H, CH ₂ -CO); 3.50 and 3.72 (2dd, 1H, CH ₂ -CO); 5.12 (dd, 1H, CO-CH-C H _2nd - CO); 6.95 (m, 2H, aryl-H); 7.15 - 7.60 (m, 5H, aryl-H): 7.95 ppm (m, 2H, aryl-H).

Example 9 2- (4-fluorophenyl) -3-phenyl-8- (2-propyl) -5,6,7,8, -tetrahydroindolizine

• Ausbeute: 24,8 g (83% der Theorie)
• Fp.: 112 - 114°C
• 'H-NMR (CDCl₃): δ= 0.92 und 1,07 (2d, 6H, CH₃); 1,45 - 1,55 (m, 1H, CH₂-CH-CH(CH₃)₂); 1,65 - 2,10 (m, 3H, CH₂-CH₂-CH-CH(CH₃)₂); 2,30 (m, 1H, CH(CH₃)_z; 2,85 (m, 1H, CH-CH(CH₃)₂); 3,55 -3,85 (m, 2H, N-CH₂); 6,15 (s, 1H, Pyrrol-H); 6,85 (m, 2H, Aryl-H); 7,10 (m, 2H, Aryl-H); 7,30 ppm (m, 5H, Aryl-H).

32.4 g (89 mmol) of 5,8-dioxo-7- (4-fluorophenyl) -8-phenyl-4- (2-propyl) octanoic acid nitrile (Example 8) are in 400 ml of methanol in the presence of 5 g of Raney -Carbon hydrogenated at a temperature of 80-90 C under a pressure of 50-60 bar hydrogen until the end of the hydrogen uptake. The precipitated crystals are dissolved by adding acetone. After filtering off the catalyst, the mixture is concentrated and the residue is recrystallized from ethanol.

• Yield: 24.8 g (83% of theory)
• Mp: 112-114 ° C
• 'H NMR (CDCl ₃ ): δ = 0.92 and 1.07 (2d, 6H, CH ₃ ); 1.45 - 1.55 (m, 1H, CH ₂ -CH-CH (CH ₃ ) ₂ ); 1.65 - 2.10 (m, 3H, CH ₂ -CH ₂ -CH-CH (CH ₃ ) ₂ ); 2.30 (m, 1H, CH (CH ₃ ) _z ; 2.85 (m, 1H, CH-CH (CH ₃ ) ₂ ); 3.55 -3.85 (m, 2H, N-CH ₂ ) ; 6 ,1 5 ( s, 1H, pyrrole-H); 6.85 (m, 2H, Ary lH ); 7.10 (m, 2H, aryl-H) ; 7 , 30 ppm (m, 5H, aryl-H).

Example 10 (E) -3- [2- (4-fluorophenyl) -3-phenyl-8- (2-propyl) -5,6,7,8-tetrahydroindolizin-1-yl] prop-2-enal

• Ausbeute: 14,5 g (80 % der Theorie)
• Fp.: 164-165°C
• ¹H-NMR (CDCl₃): δ= 0,88 und 1,04 (2d, 6H, CH₃); 1,65 - 2,35 (m, 5H, N-CH₂-CH₂-CH₂-CH-CH(CH₃)₂); 3,25 (q, 1 H, CH-CH(CH₃)₂); 3,6 - 3,9 (m, 2H, N-CH₂); 5,93 (dd, 1 H, Olefin-H); 6,85 -7,30 (m, 9H, Aryl-H); 7,42 (d, ₁ H, Olefin-H); 9,40 ppm (d, ₁ H, CHO).

6.6 g (60 mmol) of 90% dimethylaminoacrolein in 35 ml of acetonitrile are added dropwise under nitrogen at -10 ° C. to a solution of 9.2 g (60 mmol) of phosphorus oxychloride in 65 ml of anhydrous acetonitrile. 15.5 g (46.5 mmol) of 2- (4-fluorophenyl) -3-phenyl-8- (2-propyl) -5,6,7,8-tetrahydroindolizine (Example 9) are added at 0 ° C. . The mixture is allowed to come to room temperature and then stirred at this temperature for 20 h. The batch is then added to an ice-cooled solution of 16 g of sodium hydroxide in 300 ml of water with vigorous stirring. The precipitated solid is washed thoroughly with alkali-free water and recrystallized from ethanol.

• Yield: 14.5 g (80% of theory)
• Mp: 164-165 ° C
• ¹ H NMR (CDCl ₃ ): δ = 0.88 and 1.04 (2d, 6H, CH ₃ ); 1.65 - 2.35 (m, 5H, N-CH ₂ -CH ₂ -CH ₂ -CH-CH (CH ₃ ) ₂ ); 3.25 (q, 1 H, CH-CH (CH _{3) 2);} 3.6 to 3.9 (m, 2H, _N-CH2); 5.93 (dd, 1H, olefin-H); 6.8 5 -7, 30th (m, 9H, aryl-H); 7.42 (d, ₁ H, olefin-H); 9.40 ppm (d, ₁ H, CHO).

Example 11 Methyl- (E) -7- [2- (4-fluorophenyl) -3-phenyl-8- (2-propyl) -5,6,7, 8-tetrahydroindolizin-1-yl] -5-hydroxy-3- oxo-hept-6-enoate

• Ausbeute: 10,6 g rötliches Öl,
• R_f = 0,32 (Cyclohexan/Aceton 2:1)

Under nitrogen, dropwise to a suspension of 0.96 g (32 mmol) of 80% sodium hydride in 50 ml of anhydrous tetrahydrofuran at 0 ° C. 3.0 g (30 mmol) of methyl acetoacetate in 20 ml of tetrahydrofuran. After 15 min. 14.4 ml (36 mmol) of a 2.5 molar solution of n-butyllithium in hexane are added dropwise at the same temperature. After 15 min at the same temperature, 7.74 g (20 mmol) of (E) -3- [2- (4-fluorophenyl) -3-phenyl-8- (2-propyl) - 5,6,7,8- tetrahydroindolizin-1-yl] -prop-2-enal (Example 10) dissolved in 100 ml of tetrahydrofuran was added dropwise. After 15 minutes, 4 g of glacial acetic acid in 40 ml of water are added dropwise. The mixture is poured onto ice water and, after the organic phase has been separated off, extracted twice with ether. The combined organic phases are washed twice with sodium hydrogen carbonate solution and twice with saturated sodium chloride solution. After drying over sodium sulfate, the mixture is concentrated. The raw product is used without further purification.

• Yield: 10.6 g of reddish oil,
• R _f = 0.32 (cyclohexane / acetone 2: 1)

Example 12 Methyl erythro- (E) -3,5-dihydroxy-7- [2- (4-fluorophenyl) -3-phenyl-8- (2-propyl) -5,6,7,8-tetrahydroindolizin-1-yl ] -hept-6-enoate

• R_f = 0,27
• ¹H-NMR (DMSO): δ = 0,79 (dd, 3H, CH₃); 0,95 (d, 3H, CH₃); 1,5 - 2,1 (m, 5H, N-CH₂-CH₂-CH₂-CH-CH-(CH₃)₂); 2,20 - 2,45 (m, 2H, CH₂-COOCH₃); 3,55 (s, 3H, COOCH₃); 3,65 - 4,15 (m, 4H, N-CH2 und 2 CH-(OH)); 5,10 - 5,35 (m, 1 H, Olefin-H); 6,28 (dd, 1 H, Olefin-H); 6,9 - 7,3 ppm (m, 9H, Aryl-H).

Under nitrogen, dropwise to a solution of 10.6 g (20 mmol) of methyl- (E) -7- [2- (4-fluorophenyl) -3-phenyl) -8- (2-propyl) -5,6, 7,8-tetrahydroindolizin-1-yl] -5-hydroxy-3-oxo-hept-6-enoate (Example 11) in 100 ml of anhydrous tetrahydrofuran, add 24 ml (24 mmol) of a 1 molar solution of triethylborane in hexane at room temperature , passes air through the solution for 5 min and then cools to -80 ° C. 0.9 g (24 mmol) of sodium borohydride are added and 13.4 ml of methanol are slowly added dropwise, and the mixture is stirred at -75 ° C. for 15 min and at -30 C for 15 min. A solution of 65 ml of 30% hydrogen peroxide is then added dropwise in 130 ml of water. In the course of the addition, the temperature is allowed to rise to room temperature. After phase separation, the mixture is extracted with ethyl acetate. The combined organic phases are washed twice with sodium hydrogen carbonate solution and twice with saturated sodium chloride solution. After drying over sodium sulfate and concentration, the mixture is chromatographed on 250 g of silica gel (35-70 μm) using cyclohexane / acetone (2: 1). Yield: 6.4 g (63% of theory, over 2 steps), amorphous solid.

• R _f = 0.27
• ¹ H NMR (DMSO): δ = 0.79 (dd, 3H, CH ₃ ); 0.95 (d, 3H, CH _3); 1.5 - 2.1 (m, 5H, N-CH ₂ -CH ₂ -CH ₂ -CH-CH- (CH ₃ ) ₂ ); 2.20 - 2.45 (m, 2H, CH ₂ -COOCH ₃ ); 3.55 (s, 3H, COOCH ₃ ); 3.65 - 4.15 (m, 4H, NC H2 u nd 2 CH- (OH)); 5.10 - 5.35 (m, 1H, olefin-H); 6.28 (dd, 1H, olefin-H); 6.9-7.3 ppm (m, 9H, aryl-H).

Example 13 2-Acetyl-5-cyano-2-ethyl-pentanoic acid tert-butyl ester

• Ausbeute: 104,3 g (63% der Theorie)
• ¹H-NMR (CDCl₃): δ = 0,78 (t, 3H, CH₂-CH₃); 1,45 (s, 9H, OC(CH₃)₃); 1,8 - 2,0 (m, 6H, CH₂-CH₂-CH₂-CN, CH₂-CH₃); 2,13 (s, 3H, CH₃CO); 2,36 ppm (t, 2H, CH_z-CN).

121 g (0.65 mol) of tert-butyl 2-ethyl-3-oxo-butanoate are added dropwise to a suspension of 21.5 g (0.715 mol) of 80% sodium hydride in 450 ml of anhydrous dioxane under nitrogen. 105.8 g (0.715 mol) of 4-bromo-butyronitrile are then added dropwise at a temperature of 60 ° C. and the mixture is heated under reflux for 48 hours. After cooling, 50 ml of methanol are added dropwise, the sodium bromide which has precipitated is filtered off and the mixture is concentrated. The residue is filtered through silica gel with methylene chloride.

• Yield: 104.3 g (63% of theory)
• ¹ H NMR (CDCl ₃ ): δ = 0.78 (t, 3H, CH ₂ -CH ₃ ); 1.45 (s, 9H, OC (CH _{3) 3);} 1.8 - 2.0 (m, 6H, CH ₂ -CH ₂ -CH ₂ -CN, CH ₂ -CH ₃ ); 2.13 (s, 3H, CH ₃ CO); 2.36 pp m ( t, 2H, CH _z -CN).

Example 14 4-ethyl-5-oxo-heptanoic acid nitrile,

• Ausbeute: 41,1 g (67 % der Theorie)
• Kp: = 130-135° C/4 mbar
• ¹H-NMR (CDCI₃): δ = 0,89 (t, 3H, CH₂-CH₃); 1,5 - 1,8 (m, 6H, CH₂-CH₂-CH₂-CN, CH₂-CH₃); 2,13 (s, 3H, CH₃-CO); 2,36 (t, 2H, CH₂-CN); 2,57 ppm (m 1 H, CO-CH).

101.2 g (0.4 mol) of 2-acetyl-5-cyano-2-ethyl-pentanoic acid t-butyl ester are placed in a distillation apparatus together with 0.4 g of 4-toluenesulfonic acid and slowly heated to 150.degree. This temperature is maintained until the end of gas evolution. It is then distilled in vacuo.

• Yield: 41.1 g (67% of theory)
• Kp: = 130-135 ° C / 4 mbar
• ¹ H NMR (CDCI ₃ ): δ = 0.89 (t, 3H, CH ₂ -CH ₃ ); 1.5-1.8 (m, 6H, CH ₂ -CH ₂ -CH ₂ -CN, CH ₂ -CH ₃ ); 2.13 (s, 3H, CH ₃ -CO); 2.36 (t, 2H, CH ₂ -CN); 2.57 ppm (m 1 H, CO-CH).

Example 15 (E) -5-ethyl-8- (4-fluorophenyl) -6-oxo-oct-7-enenitrile

• Ausbeute: 39.4 g (58% der Theorie)
• 'H-NMR (CDCl₃): δ = 0,90 (t, 3H, CH₃); 1,5 - 1,9 (m, 6H, CH₂-CH₂-CH₂-CN, CH₂-CH₃); 2,35 (t, 2H, CH₂-CN); 2,75 (m, 1H, CO-CH); 6,75 (d, 1H, Olefin-H); 7,0 - 7,2 (m, 2H, Aryl-H); 7,5-7,7 ppm (m, 3H, 2 Aryl-H und 1 Olefin-H).

Analogously to Example 7, the title compound is obtained from 40.3 g (0.263 mol) of 4-ethyl-5-oxo-heptanoic acid nitrile and 32.6 g (0.263 mol) of 4-fluorobenzaldehyde.

• Yield: 39.4 g (58% of theory)
• 'H NMR (CDCl ₃ ): δ = 0.90 (t, 3H, CH ₃ ); 1.5 - 1.9 (m, 6H, CH ₂ -CH ₂ -CH ₂ -CN, CH ₂ -CH ₃ ); 2.35 (t, 2H, CH ₂ -CN); 2.75 (m, 1H, CO-CH); 6.75 (d, 1H, olefin-H); 7.0 - 7.2 (m, 2nd H, Aryl-H); 7.5 - 7.7 ppm (m, 3H, 2 aryl-H and 1 olefin-H).

Example 16 6,9-Dioxo-5-ethyl-8- (4-fluorophenyl) -9-phenyl-nonanoic acid nitrile

• Ausbeute: 40,9 g (75% der Theorie)
• 'H-NMR (CDCI₃): δ = 0,81 und 0,88 (2t, 3H, CH₃); 1,3 -1,9 (m, 6H, CH₂-CH₂-CH₂-CN, CH₂-CH₃); 2,3 (m, 2H, CH₂CN); 2,45 und 2,55 (2 m, 1 H, CO-CH); 2,65 - 2,85 (2 dd, 1 H, CO-CH-CH₂-CO); 3,40 -3,70 (2dd, 1H, CO-CH-CH₂-CO); 6,95 (m, 2H, Aryl-H); 7,15 - 7,60 (m, 5H, Aryl-H); 7,95 ppm (m, 2H, Aryl-H).

Analogously to Example 8, 39 g (0.15 mol) of (E) -5-ethyl-8- (4-fluorophenyl) -6-oxo-oct-7-enenitrile (Example 15) and 21.2 g (0 , 2 mol) benzaldehyde the title compound.

• Yield: 40.9 g (75% of theory)
• 'H NMR (CDCI ₃ ): δ = 0.81 and 0.88 (2t, 3H, CH ₃ ); 1.3 -1.9 (m, 6H, CH ₂ -CH ₂ -CH ₂ -CN, CH ₂ -CH ₃ ); 2.3 (m, 2H, CH ₂ CN); 2.45 and 2.55 (2 m, 1H, CO-CH); 2.65 - 2.85 (2 dd, 1H, CO -C H- CH ₂ -CO); 3, 40 -3.70 (2dd, 1H, CO-CH-CH ₂ -CO); 6.95 (m, 2H, aryl-H); 7.15 - 7.60 (m, 5H, aryl-H); 7.95 ppm (m, 2H, aryl-H).

Example 17 9-ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro-9H-pyrrolo- [1,2-a] azepine

• Ausbeute: 20,4 g (56% der Theorie)
• Fp.: 142 - 143° C
• 'H-NMR (CDCI₃): δ = 1,09 (t, 3H, CH₃); 1,25 - 2,15 (m 8H, C-CH₂-C); 2,60 (m, 1H, CH-CH₂-CH₃); 3,65 und 3,97 (m, 2H, N-CH₂); 6,06 (s, 1 H, Pyrrol-H); 6,79 (t, 2H, Aryl-H); 6,95 - 7,45 ppm (m, 7H, Aryl-H).

Analogously to Example 9, the title compound is obtained from 40 g (0.109 mol) of 6.9 dioxo-5-ethyl-8- (4-fluorophenyl) -9-phenylnononitrile (Example 16).

• Yield: 20.4 g (56% of theory)
• Mp: 142-143 ° C
• 'H NMR (CDCI ₃ ): δ = 1.09 (t, 3H, CH ₃ ); 1.25 - 2.15 (m 8H, C-CH ₂ -C); 2.60 (m, 1H, CH-CH ₂ -CH _3); 3.65 and 3.97 (m, 2H, _N-CH2); 6.06 (s, 1H, pyrrole-H); 6.79 (t, 2H, aryl-H); 6.95 - 7.45 ppm (m, 7H , Aryl-H).

Example 18 (E) -3- [9-Ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro-9H-pyrrolo- (1,2-a] azepin-1-yl ] -prop-2-enal

• Ausbeute: 13,7 g (59% der Theorie:
• Fp.: 138 - 139 C
• ¹H-NMR (CDCl₃): δ = 1,00 (t, 3H, CH₃); 1,5 - 2,2 (m, 8H, C-CH₂-C); 3,40 (m, 1H, CH-CH₂-CH₃); 3,72 und 4,08 (2 dd, 2H, N-CH₂); 5,78 (dd, 1 H, Olefin-H); 6,88 (t, 2H, Aryl-H); 7,05 (m, 5H, Aryl-H); 7,25 (m, 2H, Aryl-H); 7,45 (d, 1 H, Olefin-H); 9,40 ppm (d, 1 H, CHO).

Analogously to Example 4, 20 g (60 mmol) of 9-ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro-9H-pyrrolo- [1,2-a] - azepine (Example 17) the title compound.

• Yield: 13.7 g (59% of theory:
• M.p .: 138-139 c
• ¹ H NMR (CDCl ₃ ): δ = 1.00 (t, 3H, CH ₃ ); 1.5 - 2.2 (m, 8H, C-CH ₂ -C); 3.40 (m, 1H, CH-CH ₂ -CH _3); 3.72 and 4.08 (2 dd, 2H, _N-CH2); 5.78 (dd, 1H, olefin-H); 6.88 (t, 2H, aryl-H); 7.05 (m, 5H, ar yl- H); 7.25 (m, 2H, aryl-H); 7.45 (d, 1H, olefin-H); 9.40 ppm (d, 1H, CHO).

Example 19 Methyl- (E) -7- [9-ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro-9H-pyrrolo [1,2-a] azepine-1- yl] -5-hydroxy-3-oxo-hept-6-enoate

• Ausbeute: 5,0 g rötliches Öl
• R_f = 0,26 (Cyclohexan/Aceton 2:1)

Analogously to Example 11, 3.87 g (10 mmol) of (E) -3- [9-ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro-9H-pyrrolo- [ 1,2-a] azepin-1-yl] prop-2-enal (Example 18) the title compound.

• Yield: 5.0 g of reddish oil
• R _f = 0.26 (cyclohexane / acetone 2: 1)

Example 20 Methyl erythro- (E) -3,5-dihydroxy-7- [9-ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro-9H-pyrrolo- [1, 2-a] azepin-1-yl] hept-6-enoate

• Ausbeute: 3,2 g (65% der Theorie, über 2 Stufen) amorpher Feststoff
• R_f = 0.19 (Cyclohexan / Aceton 2:1)
• 'H-NMR (DMSO) : δ = 0.94 (m, 3H, CH₃); 1,3 - 2,1 (m, 8H, C-CH₂-C); 2,25 - 2,45 (m, 2H, CH₂-COOCH₃); 3,58 (s, 3H, COOCH₃); 3,60 - 4,15 (m, 4H, N-CH₂ und 2 CH(OH)); 5,20 (ddd, 1 H, Olefin-H); 6,28 (d, 1 H, Olefin-H); 6,90 - 7,35 ppm.(m, 9H, Aryl_-H).

Analogously to Example 12, 5.0 g (10 mmol) of methyl erythro- (E) -7- [9-ethyl-2- (4-fluorophenyl) -3-phenyl-5,6,7,8-tetrahydro are obtained -9H-pyrrolo- [1,2-a] azepin-1-yl] -5-hydroxy-3-oxo-hept-6-enoate (Example 19) the title compound.

• Yield: 3.2 g (65% of theory, over 2 steps) amorphous solid
• R _f = 0.19 (cyclohexane / acetone 2: 1)
• 'H NMR (DMSO): δ = 0.94 (m, 3H, CH ₃ ); 1.3 - 2.1 (m, 8H, C-CH ₂ -C); 2.25 to 2.45 (m, 2H, CH ₂ -COOCH _3); 3.58 (s, 3H, COOCH ₃ ); 3.60 - 4.15 (m, 4H, N-CH ₂ and 2 CH (OH)); 5.20 (ddd, 1H, olefin H); 6.28 (d, 1H, olefin-H); 6.90 - 7.35 ppm. (M, 9H, aryl _- H).

Examples of use Example 21

The enzyme activity determination was modified according to GC Ness et al., Archives of Biochemistry and Biophysics 197, 493-499 (1979). Male Ricorats (body weight 300-400 g) were treated for 11 days with altromin powder feed, to which 40 g cholestyramine / kg feed was added. After decapitation, the liver was removed from the animals and placed on ice. The livers were crushed and in the Potter-Elvejem homogenizer 3 times in 3 volumes of 0.1 m sucrose, 0.05 m KCI, 0.04 m K _x Hy phosphate, 0.03 m ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE) - Buffer pH 7.2, homogenized. The mixture was then centrifuged for 15 minutes to 15,000 ^* g and the sediment was discarded. The supernatant was sedimented at 100,000 g for 75 minutes. The pellet was taken up in 1/4 volume of SPE buffer, homogenized again and then centrifuged again at 100,000 g for 60 minutes. The pellet was taken up with 5 times its volume of SPE buffer, homogenized and frozen and stored at -78 ° C. (= enzyme solution).

For the test, the test compounds (or mevinolin as reference substance) were dissolved in dimethylformamide with the addition of 5% by volume of 1N NaOH and used in the enzyme test with 10 μl in various concentrations. The test was started after 20 minutes of pre-incubation of the compounds with the enzyme at 37 ° C. The test batch was 0.380 ml and contained 4 μmol glucose-6-phosphate, 1.1 mg bovine serum albumin, 2.1 μmol dithiothreitol, 0.35 μmol NADP, 1 unit glucose-6-phosphate dehydrogenase, 35 μmol K _x hy-phosphate PH 7 , 2, 20 ul enzyme preparation and 56 nmol of 3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3- ¹⁴ C) 100 000 dpm.

After incubation for 60 minutes at 37 ° C., the mixture was centrifuged and 600 μl of the supernatant were applied to a column filled with 0.7 × 4 cm with a 5-chloride 100-200 mesh (anion exchanger). It was distilled with 2 ml. Wash the water and add 3 ml Aquasol to the run-through plus wash water and counted in the LKB scintillation counter. IC ₅₀ values were determined by plotting the percentage inhibition against the concentration of the compound in the test by intrapolation. To determine the relative inhibitory potency of the ICso-value of the reference substance mevinolin was set at 100 and compared with the simultaneously determined IC _so value of the test compound.

Example 22

The serum cholesterol-lowering effect of the compounds according to the invention on the blood cholesterol values in dogs was found in feeding experiments lasting several weeks. For this purpose, the substance to be examined was once daily in a capsule healthy beagle dogs together with the food p.o. for a period of several weeks. given. The feed was also present during the entire trial period, i.e. Before, during and after the application period, cholestryamine (4 g / 100 g feed) was added to the substance to be examined as a bile acid sequestrant.

Venous blood was drawn from the dogs twice a week and the serum cholesterol was determined enzymatically using a commercially available test kit. The serum cholesterol values during the application period were compared with the serum cholesterol values before the application period (control).

Claims (15)

1. Substituted fused pyrroles of the general formula (I)

in which R ^{I -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - are} identical or different and stand for alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, R ² - heteroaryl means that up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, Alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or can be substituted by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ , R ^{8 - have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ . R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, the heteroaryl and aryl radicals being the same as the last 3 substituents or can be substituted differently by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R ³ , R ", R ⁵ , R ^{6 are the} same or different and - mean hydrogen, or - mean cycloalkyl, or - Alkyl, which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR'R ⁸ , in which R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are the same or up to 3 may be differently substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ and R ^{8 have} the meaning given above, or - Aryl mean that can be substituted up to 5 times by the same or different means by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ can in what R ^{9 - represents} hydrogen, alkyl, AryJ, carbamoyl, alkoxycarbonyl, X is a group of the formula -CH ₂ -CH ₂ - or -CH = CH-, A - a group of the formula

means. wherein R ¹⁰ - represents hydrogen or alkyl, and R "- stands for hydrogen, or - represents alkyl, aralkyl or aryl, or - stands for a cation, Y - means a bond, or - A group of the formula -NR ¹² means in which R ' ^{2 - represents} hydrogen or alkyl, Z is a group of the formula -CH = CH- or -CH ₂ -, or a sulfur atom, oxygen atom, or - for a group of the formula -NR ' ² , wherein R ^{12 has} the meaning given above, and n and m are the same or different and - represent a number 0, 1, 2, 3 or 4. 2. Substituted fused pyrroles according to claim 1 wherein R '- thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl or benzoxidazolyl can be substituted in the same way or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different manner by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ , where R ⁷ and R ^{8 are} identical or different and are lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl, R ^{Z -} thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2 can be substituted in the same way or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different manner by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR7R ⁸ , where R ⁷ and R ^{8 have} the meaning given above, - or cyclopropyl, cyclopentyl or cyclohexyl, or - Lower alkyl means that can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ and R ^{8 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio , Benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, it being possible for the heteroaryl and aryl radicals mentioned to be substituted up to 2 times identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, R ³ . R ⁴ , R ⁵ , R ^{6 may be the} same or different, and - hydrogen, or - mean cyclopropyl, cyclopentyl or cyclohexyl, or - Lower alkyl, which can be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR'R ⁸ , in which R7 and R ^{8 have} the meaning given above, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio Benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, it being possible for the heteroaryl and aryl radicals mentioned to be substituted up to 2 times identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, or - means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which up to 2-fold may be substituted identically or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or - Phenyl or naphthyl, which can be substituted up to 4 times in the same or different manner by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylsulfonyl, phenyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ , where R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which can optionally be interrupted by an oxygen atom, a sulfur atom or by a group of the formula -NR ⁹ , in which R ^{9 - represents} hydrogen, lower alkyl, phenyl, benzyl or lower alkoxycarbonyl, X - a group of the formula -CH = CH- means A - a group of the formula

means what R '° - represents hydrogen or lower alkyl, R "- stands for hydrogen, or - represents lower alkyl or phenyl, or - stands for a physiologically compatible cation, or - stands for benzyl, Y - means a bond, or - A group of the formula -NR ' ² , wherein R ' ^{2 - represents} hydrogen or lower alkyl, Z is a group of the formula -CH = CH- or -CH ₂ -, or - a sulfur atom, oxygen atom or - A group of the formula -NR ' ² , wherein R ' ^{2 has} the meaning given above, and n and m are the same or different and - one of the numbers 0, 1, 2, 3 or 4 means. 3. Substituted fused pyrroles according to claims 1 and 2 wherein R 'is pyridyl, pyrimidyl, quinolyl or isoquinolyl, which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or - Phenyl means that up to 3 times the same or different substitution can be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, butoxycarbonyl, butoxy , R ² denotes pyridyl, pyrimidyl, quinolyl or isoquinolyl, which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or - Phenyl means that up to 3 times the same or different substitution can be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, butoxycarbonyl, butoxy , or - Cyclopropyl, cyclopentyl or cyclohexyl, or - Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert. Butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, pyridyl, pyridyl, pyridylyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl , Phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, _R 3, R ⁴ , R ⁵ and R ^{6 are the} same or different and - mean hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or - Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tr.butylsulfoxy, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methylbutylifoxyoxy, methoxycarbonyl, methylbutylifoxy, oxyoxyoxy , Isobutoxycarbonyl, tert.butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR ⁷ R ⁸ , where R ⁷ and R ^{8 are the} same or different and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinoline, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, the heteroaryl and aryl radicals mentioned being fluorine, chlorine, methyl, ethyl, propyl Isopropyl, isobutyl, tert. Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl or trifluoromethoxy may be substituted, or - Thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzothiazolyl, where the said radicals are methyl, eth, by fluorine , Isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert may be substituted, or - Phenyl mean up to 3 times the same or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, tert.-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.-butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfylyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, tertyl Benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl. Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl or can be substituted by a group -NR ⁷ R ⁸ , where R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which can optionally be interrupted by an oxygen atom, a sulfur atom or by a group of the formula -NR ⁹ , in which R ^{9 - represents} hydrogen, methyl, ethyl, proyl, isopropyl, tert-butyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl, X - a group of the formula -CH = CH- means A - a group of the formula

means what R '° - represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, R "- represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or - represents a sodium, potassium, calcium or magnesium or ammonium ion, Y - means a bond, or - A group of the formula -NR ' ² , wherein R ¹² - represents hydrogen, methyl, ethyl, propyl, isopropyl or tert-butyl, Z is a group of the formula -CH = CH- or -CH ₂ -, or - a sulfur atom, oxygen atom or - A group of the formula -NR ' ² , wherein R ' ^{2 has} the meaning given above, and m and n are the same or different and - one of the numbers 0, 1, 2, 3 or 4 mean. 4. Substituted fused pyrroles according to claims 1 to 3 for therapeutic treatment. 5. Process for the preparation of substituted fused pyrroles of the general formula

in which R ¹ - heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, R ^{Z -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{s - have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR'R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ , R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals up to the latter 3 can be substituted in the same way or differently by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, _R 3, _R ⁴ , R ⁵ , R ^{6 are the} same or different and - mean hydrogen, or - mean cycloalkyl, or - Alkyl, which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are the same or up to 3 may be differently substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ and R ^{8 have} the meaning given above, or - Aryl mean that can be substituted up to 5 times by the same or different means by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may optionally be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ , in which R ^{9 -} for hydrogen. Alkyl, aryl, carbamoyl, alkoxycarbonyl, X is a group of the formula -CH ₂ -CH ₂ - or -CH = CH-, A - a group of the formula

means what R '° - represents hydrogen or alkyl, and R "- stands for hydrogen, or - represents alkyl, aralkyl or aryl, or - stands for a cation, Y - means a bond, or - A group of the formula -NR ¹² means in which R ' ^{2 - represents} hydrogen or alkyl, Z - represents a group of the formula -CH = CH- or -CH ₂ , or - for a sulfur atom, oxygen atom, or - represents a group of the formula -NR ' ² , wherein R ' ^{2 has} the meaning given above, and n and m are the same or different and represent a number 0, 1, 2, 3 or 4, characterized in that ketones of the general formula (VIII)

in which R ¹ , ^{R2, R3, R4, RS, R6, Y, Z, m} and ^{n have} the meaning given above and _R ' ^{3 - represents} alkyl, reduced, and in the case of the production of the acids, the esters are saponified, in the case of the production of the lactones, the carboxylic acids are cyclized, in the case of the preparation of the salts, either the esters or the lactones are saponified, in the case of the preparation of the ethane compound (X = -CH ₂ -CH ₂ -) the ethene compound (X = -CH = CH-) is hydrogenated by customary methods, and optionally separates isomers. 6. The method according to claim 5, characterized in that the reduction in the temperature range of -80 to +30 C is carried out. 7. Ketones of the general formula (VIII)

in which R '- heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, R ^{2 -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{s - have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ , R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio, or aralkylsulfonyl, the heteroaryl and aryl radicals being the latter to the latter 3 times the same or different can be substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, _R 3, _R ⁴ , _R ⁵ , R ^{6 are the} same or different and - mean hydrogen, or - mean cycloalkyl, or - Alkyl, which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluomethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, wherein the heteroaryl and aryl groups of up to 3 times by identical or different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl , Alkoxy, alkylthio or alkylsulfonyl may be substituted, or - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R7 and R ^{8 have} the meaning given above, or Mean aryl, which can be substituted up to 5 times in the same or different ways by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, Arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or a group of the formula -NR ⁷ R ^8, wherein R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may optionally be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ , in which R ^{9 - represents} hydrogen, alkyl, aryl, carbamoyl, alkoxycarbonyl, Y - means a bond, or - A group of the formula -NR ' ² means in which R ' ^{2 - represents} hydrogen or alkyl, Z - is a group of the formula -CH = CH- or -CH ₂ , or - a sulfur atom, oxygen atom, or - A group of the formula -NR ¹² means, wherein R ' ^{2 has} the meaning given above, n and m are the same or different and - represent a number 0, 1, 2, 3 or 4, and R ¹³ means alkyl. 8. Process for the preparation of ketones of the general formula

in which R ^{I -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dial kylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR'R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, R ^{2 -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ and R ^{8 - have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ , R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio, or aralkylsulfonyl, the heteroaryl and aryl radicals being the latter to the latter 3 times the same or different can be substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R3, R ⁴ , R ⁵ , R ^{6 are the} same or different and - mean hydrogen, or - mean cycloalkyl, or - Alkyl, which can be substituted by halogen, 'cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluomethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are the same or up to 3 may be differently substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ and R ^{8 have} the meaning given above, or - Aryl mean that can be substituted up to 5 times by the same or different means by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ can in what R ^{9 - represents} hydrogen, alkyl, aryl, carbamoyl, alkoxycarbonyl, Y - means a bond, or - A group of the formula -NR ' ² means wherein R ' ^{2 - represents} hydrogen or alkyl, Z - is a group of the formula -CH = CH- or -CH ₂ , or - a sulfur atom, oxygen atom, or - A group of the formula -NR ²² , wherein R ' ^{2 has} the meaning given above, n and m are the same or different and - stand for a number 0, 1, 2, 3 or 4, and _{R '} ³ denotes alkyl, characterized in that one Aldehydes of the general formula (IX)

in which R ', _R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Z, m and n have the meaning given above, in inert solvents with acetoacetic esters of the general formula (X)

in which R ' ^{3 has} the meaning given above, in the presence of bases. 9. Aldehydes of the general formula

in which R '- heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, R ^{2 -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR'R ⁸ , in which R ⁷ , R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio, or aralkylsulfonyl, the heteroaryl and aryl radicals being the latter to the latter 3 times the same or different can be substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R ³ , R ⁴ , R ^S , R ^{6 are the} same or different and - mean hydrogen, or - mean cycloalkyl, or - Alkyl, which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluomethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are the same or up to 3 may be differently substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ and R ^{8 have} the meaning given above, or - Aryl mean that can be substituted up to 5 times by the same or different means by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ can in what R ^{9 - represents} hydrogen, alkyl, aryl, carbamoyl, or alkoxycarbonyl, Y - means a bond, or - A group of the formula -NR ¹² means in which R ¹² - represents hydrogen or alkyl, Z - is a group of the formula -CH = CH- or -CH ₂ , or - a sulfur atom, oxygen atom, or - A group of the formula -NR ¹² means, wherein R ' ^{z has} the meaning given above, and n and m are the same or different and - stand for a number 0, 1, 2, 3 or 4. 10. Process for the preparation of aldehydes of the general formula

in which R '- heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - are the} same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR'R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, R ^{2 -} heteroaryl means up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ , R ^{8 - have} the meaning given above, or - Aryl means that up to 5-fold can be substituted identically or differently by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or - Cycloalkyl means or - Alkyl means which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , in which R ⁷ , R ^{8 - have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio, or aralkylsulfonyl, the heteroaryl and aryl residues of the latter being the latter 3 times the same or different can be substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, _R 3, _R ⁴ , _R ⁵ , R ^{6 are the} same or different and - mean hydrogen, or - mean cycloalkyl, or - Alkyl, which can be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluomethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ , R ^{8 have} the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are the same or up to 3 may be differently substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or - Heteroaryl mean up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁷ R ⁸ can be substituted, wherein R ⁷ and R ^{8 have} the meaning given above, or Mean aryl, which can be substituted up to 5 times by the same or different means by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, Trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meaning given above, or R ³ and R ⁴ and / or R ⁵ and R ⁶ each together form a ring which may be interrupted by an oxygen atom, a sulfur atom or a group of the formula -NR ⁹ can in what R ^{9 - represents} hydrogen, alkyl, aryl, carbamoyl, or alkoxycarbonyl, Y - means a bond, or - a group of the formula -NR ' ² means in which R ' ^{2 - represents} hydrogen or alkyl, Z - is a group of the formula -CH = CH- or -CH ₂ , or - a sulfur atom, oxygen atom, or - A group of the formula -NR ¹² means, wherein R ' ^{2 has} the meaning given above, and n and m are identical or different and represent a number 0, 1, 2, 3 or 4, characterized in that substituted pyrroles of the general formula (XI)

in which R ¹ , R ² , R ³ , R ⁴ , R ^S , R ⁶ , Y, Z, m and n have the meaning given above, in inert solvents in the presence of auxiliaries with N, N-dialkylaminoacroline of the formula (XII)

in which Alkyl - represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. 11. Medicaments containing substituted fused pyrroles according to claims 1 to 3. 12. Medicament according to claim 11, characterized in that it contains 0.5 to 98 wt .-% substituted fused pyrroles based on the total mixture. 13. Use of substituted fused pyrroles according to claims 1 to 3 for the treatment of diseases. 14. Use of substituted fused pyrroles according to claims 1 to 3 for the manufacture of medicaments. 15. Use according to claim 14 for the production of inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase.